Basic Concepts They Keep Changing

Leslie Z Benet PhD Professor of Bioengineering and Therapeutic Sciences

Schools of Pharmacy and Medicine UCSF 2nd MENA Regulatory Conference

on Bioequivalence Biowaivers Bioanalysis Dissolution and Biosimilars

Amman September 15 2015

Forty-three years ago (1972) the majority of published pharmacokinetic studies

were carried out with salicylic acid

bull Because the drug was given in large doses bull And we had a colorimetric assay using

the Trinder reaction that allowed us to measure plasma and urinary concentrations

bull And all the pharmacokinetic analyses were in terms of rate constants (ie tfrac12 s)

Half-Life observations in 1972 that could not be explained by PK theory then

A number of experimental observations in the late 1960s early 1970s could not be explained by the pharmacokinetic theory available at the time For example von Bahr et al (1970) observed that for rats receiving phenobarbital as an enzyme inducing agent the half-life of iv phenylbutazone was decreased both in vitro in liver microsomes and in vivo in whole animals versus that observed in non-induced animals

However for the drug desipramine although half-life

was decreased in microsomes from phenobarbital induced rats no change in plasma disappearance (tfrac12) was noted in vivo for this drug given iv between rats induced with phenobarbital and control rats

Half-Life observations in 1972 that could not be explained by PK theory then

Swedish workers in the late 1960rsquos had studied a number of anxiolytics and anti-inflammatory drugs in rat liver microsomes and in whole animals prior to and after enzyme induction with phenobarbital In some cases half-life of the drug was decreased in both the microsomes and in vivo but in other cases in vitro induction was seen but no in vivo induction

Dr E Kruger-Theimer had investigated the renal

elimination of highly protein bound sulfonamides in healthy volunteers In some cases adding a drug that competed for protein binding in vitro caused a half-life decrease in vivo but for other sulfonamides the in vitro decrease in protein binding yielded no in vivo changes

So in 1972 what was wrong with Pharmacokinetics

It appeared to have no relationship with clinically meaningful parameters that could help in making

drug dosing decisions or that could account for differences in physiology and pathology

For example at Steady-State

RATE IN = RATE OUT

AVAILABILITY x DOSING RATE = x AVERAGE CONCENTRATION

F x DOSING RATE = x TARGET CONCENTRATION

A In Therapeutics At steady-state

Rate In = Rate Out Availability bull Dosing Rate = Clearance bull Concentration at steady-state F bull Doseτ = CL bull Css (Eq 1)

vol time

= mass time

mass vol

Rate of elimination = QbullCA - QbullCV (Eq 2)

= Q bull

CA - CVCA

= Q bull ER (Eq 3)

CL organ =

Q bull CA - Q bull CVCA

mlmin bull massml

extraction ratio

We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that we

borrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline

bull Extraction Ratio was defined as a function of three parameters

a blood flow to the elimination organ b the intrinsic ability of the organ to

eliminate the unbound drug if there were no flow and protein binding limitations

c the fraction of drug unbound in the blood

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

Eq 4

Q bull ER

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

where fub is the unbound fraction of drug in blood

CLorgan cong Q ie CL and tfrac12 independent of CLint and fub

fub bull CLint gtgt Q

Q gtgt fub bull CLint

CL organ cong fub bull CL int

Clearance concepts allowed the field to develop a basic understanding and to

make predictions as to how pathological and physiological changes would

influence drug kinetics and drug dosing It provided the quantitative rational for

Clinical Pharmacology

bull Clearance was the first noncompartmental parameter

Looking at PubMed for the term ldquoDrug Clearancerdquo

bull 1972 -- there were 192 references many of them dealing with ldquomucociliary drug clearancerdquo

bull 2006 ndash there were gt29000 references bull September 13 2015 ndash 62728 references

In the previous examples we explained the change or lack of change in half-life in terms of clearance changes

AGE

Figu re 11-7 The half-life of diazepam increaseswith age from 20 to 80 years (From Rowland ampTozer s Clinical Pharmacokinetics p 230)

Age (y ears)100 20

Half-Life (hrs)

120

40

Here is an interesting change in half-life for diazepam with age Can we explain this in terms of clearance That is does metabolic clearance of diazepam decrease with age

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Forty-three years ago (1972) the majority of published pharmacokinetic studies

were carried out with salicylic acid

bull Because the drug was given in large doses bull And we had a colorimetric assay using

the Trinder reaction that allowed us to measure plasma and urinary concentrations

bull And all the pharmacokinetic analyses were in terms of rate constants (ie tfrac12 s)

Half-Life observations in 1972 that could not be explained by PK theory then

A number of experimental observations in the late 1960s early 1970s could not be explained by the pharmacokinetic theory available at the time For example von Bahr et al (1970) observed that for rats receiving phenobarbital as an enzyme inducing agent the half-life of iv phenylbutazone was decreased both in vitro in liver microsomes and in vivo in whole animals versus that observed in non-induced animals

However for the drug desipramine although half-life

was decreased in microsomes from phenobarbital induced rats no change in plasma disappearance (tfrac12) was noted in vivo for this drug given iv between rats induced with phenobarbital and control rats

Half-Life observations in 1972 that could not be explained by PK theory then

Swedish workers in the late 1960rsquos had studied a number of anxiolytics and anti-inflammatory drugs in rat liver microsomes and in whole animals prior to and after enzyme induction with phenobarbital In some cases half-life of the drug was decreased in both the microsomes and in vivo but in other cases in vitro induction was seen but no in vivo induction

Dr E Kruger-Theimer had investigated the renal

elimination of highly protein bound sulfonamides in healthy volunteers In some cases adding a drug that competed for protein binding in vitro caused a half-life decrease in vivo but for other sulfonamides the in vitro decrease in protein binding yielded no in vivo changes

So in 1972 what was wrong with Pharmacokinetics

It appeared to have no relationship with clinically meaningful parameters that could help in making

drug dosing decisions or that could account for differences in physiology and pathology

For example at Steady-State

RATE IN = RATE OUT

AVAILABILITY x DOSING RATE = x AVERAGE CONCENTRATION

F x DOSING RATE = x TARGET CONCENTRATION

A In Therapeutics At steady-state

Rate In = Rate Out Availability bull Dosing Rate = Clearance bull Concentration at steady-state F bull Doseτ = CL bull Css (Eq 1)

vol time

= mass time

mass vol

Rate of elimination = QbullCA - QbullCV (Eq 2)

= Q bull

CA - CVCA

= Q bull ER (Eq 3)

CL organ =

Q bull CA - Q bull CVCA

mlmin bull massml

extraction ratio

We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that we

borrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline

bull Extraction Ratio was defined as a function of three parameters

a blood flow to the elimination organ b the intrinsic ability of the organ to

eliminate the unbound drug if there were no flow and protein binding limitations

c the fraction of drug unbound in the blood

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

Eq 4

Q bull ER

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

where fub is the unbound fraction of drug in blood

CLorgan cong Q ie CL and tfrac12 independent of CLint and fub

fub bull CLint gtgt Q

Q gtgt fub bull CLint

CL organ cong fub bull CL int

Clearance concepts allowed the field to develop a basic understanding and to

make predictions as to how pathological and physiological changes would

influence drug kinetics and drug dosing It provided the quantitative rational for

Clinical Pharmacology

bull Clearance was the first noncompartmental parameter

Looking at PubMed for the term ldquoDrug Clearancerdquo

bull 1972 -- there were 192 references many of them dealing with ldquomucociliary drug clearancerdquo

bull 2006 ndash there were gt29000 references bull September 13 2015 ndash 62728 references

In the previous examples we explained the change or lack of change in half-life in terms of clearance changes

AGE

Figu re 11-7 The half-life of diazepam increaseswith age from 20 to 80 years (From Rowland ampTozer s Clinical Pharmacokinetics p 230)

Age (y ears)100 20

Half-Life (hrs)

120

40

Here is an interesting change in half-life for diazepam with age Can we explain this in terms of clearance That is does metabolic clearance of diazepam decrease with age

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Half-Life observations in 1972 that could not be explained by PK theory then

A number of experimental observations in the late 1960s early 1970s could not be explained by the pharmacokinetic theory available at the time For example von Bahr et al (1970) observed that for rats receiving phenobarbital as an enzyme inducing agent the half-life of iv phenylbutazone was decreased both in vitro in liver microsomes and in vivo in whole animals versus that observed in non-induced animals

However for the drug desipramine although half-life

was decreased in microsomes from phenobarbital induced rats no change in plasma disappearance (tfrac12) was noted in vivo for this drug given iv between rats induced with phenobarbital and control rats

Half-Life observations in 1972 that could not be explained by PK theory then

Swedish workers in the late 1960rsquos had studied a number of anxiolytics and anti-inflammatory drugs in rat liver microsomes and in whole animals prior to and after enzyme induction with phenobarbital In some cases half-life of the drug was decreased in both the microsomes and in vivo but in other cases in vitro induction was seen but no in vivo induction

Dr E Kruger-Theimer had investigated the renal

elimination of highly protein bound sulfonamides in healthy volunteers In some cases adding a drug that competed for protein binding in vitro caused a half-life decrease in vivo but for other sulfonamides the in vitro decrease in protein binding yielded no in vivo changes

So in 1972 what was wrong with Pharmacokinetics

It appeared to have no relationship with clinically meaningful parameters that could help in making

drug dosing decisions or that could account for differences in physiology and pathology

For example at Steady-State

RATE IN = RATE OUT

AVAILABILITY x DOSING RATE = x AVERAGE CONCENTRATION

F x DOSING RATE = x TARGET CONCENTRATION

A In Therapeutics At steady-state

Rate In = Rate Out Availability bull Dosing Rate = Clearance bull Concentration at steady-state F bull Doseτ = CL bull Css (Eq 1)

vol time

= mass time

mass vol

Rate of elimination = QbullCA - QbullCV (Eq 2)

= Q bull

CA - CVCA

= Q bull ER (Eq 3)

CL organ =

Q bull CA - Q bull CVCA

mlmin bull massml

extraction ratio

We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that we

borrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline

bull Extraction Ratio was defined as a function of three parameters

a blood flow to the elimination organ b the intrinsic ability of the organ to

eliminate the unbound drug if there were no flow and protein binding limitations

c the fraction of drug unbound in the blood

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

Eq 4

Q bull ER

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

where fub is the unbound fraction of drug in blood

CLorgan cong Q ie CL and tfrac12 independent of CLint and fub

fub bull CLint gtgt Q

Q gtgt fub bull CLint

CL organ cong fub bull CL int

Clearance concepts allowed the field to develop a basic understanding and to

make predictions as to how pathological and physiological changes would

influence drug kinetics and drug dosing It provided the quantitative rational for

Clinical Pharmacology

bull Clearance was the first noncompartmental parameter

Looking at PubMed for the term ldquoDrug Clearancerdquo

bull 1972 -- there were 192 references many of them dealing with ldquomucociliary drug clearancerdquo

bull 2006 ndash there were gt29000 references bull September 13 2015 ndash 62728 references

In the previous examples we explained the change or lack of change in half-life in terms of clearance changes

AGE

Figu re 11-7 The half-life of diazepam increaseswith age from 20 to 80 years (From Rowland ampTozer s Clinical Pharmacokinetics p 230)

Age (y ears)100 20

Half-Life (hrs)

120

40

Here is an interesting change in half-life for diazepam with age Can we explain this in terms of clearance That is does metabolic clearance of diazepam decrease with age

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Half-Life observations in 1972 that could not be explained by PK theory then

Swedish workers in the late 1960rsquos had studied a number of anxiolytics and anti-inflammatory drugs in rat liver microsomes and in whole animals prior to and after enzyme induction with phenobarbital In some cases half-life of the drug was decreased in both the microsomes and in vivo but in other cases in vitro induction was seen but no in vivo induction

Dr E Kruger-Theimer had investigated the renal

elimination of highly protein bound sulfonamides in healthy volunteers In some cases adding a drug that competed for protein binding in vitro caused a half-life decrease in vivo but for other sulfonamides the in vitro decrease in protein binding yielded no in vivo changes

So in 1972 what was wrong with Pharmacokinetics

It appeared to have no relationship with clinically meaningful parameters that could help in making

drug dosing decisions or that could account for differences in physiology and pathology

For example at Steady-State

RATE IN = RATE OUT

AVAILABILITY x DOSING RATE = x AVERAGE CONCENTRATION

F x DOSING RATE = x TARGET CONCENTRATION

A In Therapeutics At steady-state

Rate In = Rate Out Availability bull Dosing Rate = Clearance bull Concentration at steady-state F bull Doseτ = CL bull Css (Eq 1)

vol time

= mass time

mass vol

Rate of elimination = QbullCA - QbullCV (Eq 2)

= Q bull

CA - CVCA

= Q bull ER (Eq 3)

CL organ =

Q bull CA - Q bull CVCA

mlmin bull massml

extraction ratio

We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that we

borrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline

bull Extraction Ratio was defined as a function of three parameters

a blood flow to the elimination organ b the intrinsic ability of the organ to

eliminate the unbound drug if there were no flow and protein binding limitations

c the fraction of drug unbound in the blood

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

Eq 4

Q bull ER

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

where fub is the unbound fraction of drug in blood

CLorgan cong Q ie CL and tfrac12 independent of CLint and fub

fub bull CLint gtgt Q

Q gtgt fub bull CLint

CL organ cong fub bull CL int

Clearance concepts allowed the field to develop a basic understanding and to

make predictions as to how pathological and physiological changes would

influence drug kinetics and drug dosing It provided the quantitative rational for

Clinical Pharmacology

bull Clearance was the first noncompartmental parameter

Looking at PubMed for the term ldquoDrug Clearancerdquo

bull 1972 -- there were 192 references many of them dealing with ldquomucociliary drug clearancerdquo

bull 2006 ndash there were gt29000 references bull September 13 2015 ndash 62728 references

In the previous examples we explained the change or lack of change in half-life in terms of clearance changes

AGE

Figu re 11-7 The half-life of diazepam increaseswith age from 20 to 80 years (From Rowland ampTozer s Clinical Pharmacokinetics p 230)

Age (y ears)100 20

Half-Life (hrs)

120

40

Here is an interesting change in half-life for diazepam with age Can we explain this in terms of clearance That is does metabolic clearance of diazepam decrease with age

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

So in 1972 what was wrong with Pharmacokinetics

It appeared to have no relationship with clinically meaningful parameters that could help in making

drug dosing decisions or that could account for differences in physiology and pathology

For example at Steady-State

RATE IN = RATE OUT

AVAILABILITY x DOSING RATE = x AVERAGE CONCENTRATION

F x DOSING RATE = x TARGET CONCENTRATION

A In Therapeutics At steady-state

Rate In = Rate Out Availability bull Dosing Rate = Clearance bull Concentration at steady-state F bull Doseτ = CL bull Css (Eq 1)

vol time

= mass time

mass vol

Rate of elimination = QbullCA - QbullCV (Eq 2)

= Q bull

CA - CVCA

= Q bull ER (Eq 3)

CL organ =

Q bull CA - Q bull CVCA

mlmin bull massml

extraction ratio

We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that we

borrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline

bull Extraction Ratio was defined as a function of three parameters

a blood flow to the elimination organ b the intrinsic ability of the organ to

eliminate the unbound drug if there were no flow and protein binding limitations

c the fraction of drug unbound in the blood

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

Eq 4

Q bull ER

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

where fub is the unbound fraction of drug in blood

CLorgan cong Q ie CL and tfrac12 independent of CLint and fub

fub bull CLint gtgt Q

Q gtgt fub bull CLint

CL organ cong fub bull CL int

Clearance concepts allowed the field to develop a basic understanding and to

make predictions as to how pathological and physiological changes would

influence drug kinetics and drug dosing It provided the quantitative rational for

Clinical Pharmacology

bull Clearance was the first noncompartmental parameter

Looking at PubMed for the term ldquoDrug Clearancerdquo

bull 1972 -- there were 192 references many of them dealing with ldquomucociliary drug clearancerdquo

bull 2006 ndash there were gt29000 references bull September 13 2015 ndash 62728 references

In the previous examples we explained the change or lack of change in half-life in terms of clearance changes

AGE

Figu re 11-7 The half-life of diazepam increaseswith age from 20 to 80 years (From Rowland ampTozer s Clinical Pharmacokinetics p 230)

Age (y ears)100 20

Half-Life (hrs)

120

40

Here is an interesting change in half-life for diazepam with age Can we explain this in terms of clearance That is does metabolic clearance of diazepam decrease with age

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

A In Therapeutics At steady-state

Rate In = Rate Out Availability bull Dosing Rate = Clearance bull Concentration at steady-state F bull Doseτ = CL bull Css (Eq 1)

vol time

= mass time

mass vol

Rate of elimination = QbullCA - QbullCV (Eq 2)

= Q bull

CA - CVCA

= Q bull ER (Eq 3)

CL organ =

Q bull CA - Q bull CVCA

mlmin bull massml

extraction ratio

We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that we

borrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline

bull Extraction Ratio was defined as a function of three parameters

a blood flow to the elimination organ b the intrinsic ability of the organ to

eliminate the unbound drug if there were no flow and protein binding limitations

c the fraction of drug unbound in the blood

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

Eq 4

Q bull ER

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

where fub is the unbound fraction of drug in blood

CLorgan cong Q ie CL and tfrac12 independent of CLint and fub

fub bull CLint gtgt Q

Q gtgt fub bull CLint

CL organ cong fub bull CL int

Clearance concepts allowed the field to develop a basic understanding and to

make predictions as to how pathological and physiological changes would

influence drug kinetics and drug dosing It provided the quantitative rational for

Clinical Pharmacology

bull Clearance was the first noncompartmental parameter

Looking at PubMed for the term ldquoDrug Clearancerdquo

bull 1972 -- there were 192 references many of them dealing with ldquomucociliary drug clearancerdquo

bull 2006 ndash there were gt29000 references bull September 13 2015 ndash 62728 references

In the previous examples we explained the change or lack of change in half-life in terms of clearance changes

AGE

Figu re 11-7 The half-life of diazepam increaseswith age from 20 to 80 years (From Rowland ampTozer s Clinical Pharmacokinetics p 230)

Age (y ears)100 20

Half-Life (hrs)

120

40

Here is an interesting change in half-life for diazepam with age Can we explain this in terms of clearance That is does metabolic clearance of diazepam decrease with age

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Rate of elimination = QbullCA - QbullCV (Eq 2)

= Q bull

CA - CVCA

= Q bull ER (Eq 3)

CL organ =

Q bull CA - Q bull CVCA

mlmin bull massml

extraction ratio

We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that we

borrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline

bull Extraction Ratio was defined as a function of three parameters

a blood flow to the elimination organ b the intrinsic ability of the organ to

eliminate the unbound drug if there were no flow and protein binding limitations

c the fraction of drug unbound in the blood

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

Eq 4

Q bull ER

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

where fub is the unbound fraction of drug in blood

CLorgan cong Q ie CL and tfrac12 independent of CLint and fub

fub bull CLint gtgt Q

Q gtgt fub bull CLint

CL organ cong fub bull CL int

Clearance concepts allowed the field to develop a basic understanding and to

make predictions as to how pathological and physiological changes would

influence drug kinetics and drug dosing It provided the quantitative rational for

Clinical Pharmacology

bull Clearance was the first noncompartmental parameter

Looking at PubMed for the term ldquoDrug Clearancerdquo

bull 1972 -- there were 192 references many of them dealing with ldquomucociliary drug clearancerdquo

bull 2006 ndash there were gt29000 references bull September 13 2015 ndash 62728 references

In the previous examples we explained the change or lack of change in half-life in terms of clearance changes

AGE

Figu re 11-7 The half-life of diazepam increaseswith age from 20 to 80 years (From Rowland ampTozer s Clinical Pharmacokinetics p 230)

Age (y ears)100 20

Half-Life (hrs)

120

40

Here is an interesting change in half-life for diazepam with age Can we explain this in terms of clearance That is does metabolic clearance of diazepam decrease with age

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that we

borrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline

bull Extraction Ratio was defined as a function of three parameters

a blood flow to the elimination organ b the intrinsic ability of the organ to

eliminate the unbound drug if there were no flow and protein binding limitations

c the fraction of drug unbound in the blood

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

Eq 4

Q bull ER

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

where fub is the unbound fraction of drug in blood

CLorgan cong Q ie CL and tfrac12 independent of CLint and fub

fub bull CLint gtgt Q

Q gtgt fub bull CLint

CL organ cong fub bull CL int

Clearance concepts allowed the field to develop a basic understanding and to

make predictions as to how pathological and physiological changes would

influence drug kinetics and drug dosing It provided the quantitative rational for

Clinical Pharmacology

bull Clearance was the first noncompartmental parameter

Looking at PubMed for the term ldquoDrug Clearancerdquo

bull 1972 -- there were 192 references many of them dealing with ldquomucociliary drug clearancerdquo

bull 2006 ndash there were gt29000 references bull September 13 2015 ndash 62728 references

In the previous examples we explained the change or lack of change in half-life in terms of clearance changes

AGE

Figu re 11-7 The half-life of diazepam increaseswith age from 20 to 80 years (From Rowland ampTozer s Clinical Pharmacokinetics p 230)

Age (y ears)100 20

Half-Life (hrs)

120

40

Here is an interesting change in half-life for diazepam with age Can we explain this in terms of clearance That is does metabolic clearance of diazepam decrease with age

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

Eq 4

Q bull ER

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

where fub is the unbound fraction of drug in blood

CLorgan cong Q ie CL and tfrac12 independent of CLint and fub

fub bull CLint gtgt Q

Q gtgt fub bull CLint

CL organ cong fub bull CL int

Clearance concepts allowed the field to develop a basic understanding and to

make predictions as to how pathological and physiological changes would

influence drug kinetics and drug dosing It provided the quantitative rational for

Clinical Pharmacology

bull Clearance was the first noncompartmental parameter

Looking at PubMed for the term ldquoDrug Clearancerdquo

bull 1972 -- there were 192 references many of them dealing with ldquomucociliary drug clearancerdquo

bull 2006 ndash there were gt29000 references bull September 13 2015 ndash 62728 references

In the previous examples we explained the change or lack of change in half-life in terms of clearance changes

AGE

Figu re 11-7 The half-life of diazepam increaseswith age from 20 to 80 years (From Rowland ampTozer s Clinical Pharmacokinetics p 230)

Age (y ears)100 20

Half-Life (hrs)

120

40

Here is an interesting change in half-life for diazepam with age Can we explain this in terms of clearance That is does metabolic clearance of diazepam decrease with age

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

CL organ = Q bull

fub bull C LintQ + fub bull C Lint

where fub is the unbound fraction of drug in blood

CLorgan cong Q ie CL and tfrac12 independent of CLint and fub

fub bull CLint gtgt Q

Q gtgt fub bull CLint

CL organ cong fub bull CL int

Clearance concepts allowed the field to develop a basic understanding and to

make predictions as to how pathological and physiological changes would

influence drug kinetics and drug dosing It provided the quantitative rational for

Clinical Pharmacology

bull Clearance was the first noncompartmental parameter

Looking at PubMed for the term ldquoDrug Clearancerdquo

bull 1972 -- there were 192 references many of them dealing with ldquomucociliary drug clearancerdquo

bull 2006 ndash there were gt29000 references bull September 13 2015 ndash 62728 references

In the previous examples we explained the change or lack of change in half-life in terms of clearance changes

AGE

Figu re 11-7 The half-life of diazepam increaseswith age from 20 to 80 years (From Rowland ampTozer s Clinical Pharmacokinetics p 230)

Age (y ears)100 20

Half-Life (hrs)

120

40

Here is an interesting change in half-life for diazepam with age Can we explain this in terms of clearance That is does metabolic clearance of diazepam decrease with age

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Clearance concepts allowed the field to develop a basic understanding and to

make predictions as to how pathological and physiological changes would

influence drug kinetics and drug dosing It provided the quantitative rational for

Clinical Pharmacology

bull Clearance was the first noncompartmental parameter

Looking at PubMed for the term ldquoDrug Clearancerdquo

bull 1972 -- there were 192 references many of them dealing with ldquomucociliary drug clearancerdquo

bull 2006 ndash there were gt29000 references bull September 13 2015 ndash 62728 references

In the previous examples we explained the change or lack of change in half-life in terms of clearance changes

AGE

Figu re 11-7 The half-life of diazepam increaseswith age from 20 to 80 years (From Rowland ampTozer s Clinical Pharmacokinetics p 230)

Age (y ears)100 20

Half-Life (hrs)

120

40

Here is an interesting change in half-life for diazepam with age Can we explain this in terms of clearance That is does metabolic clearance of diazepam decrease with age

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Looking at PubMed for the term ldquoDrug Clearancerdquo

bull 1972 -- there were 192 references many of them dealing with ldquomucociliary drug clearancerdquo

bull 2006 ndash there were gt29000 references bull September 13 2015 ndash 62728 references

In the previous examples we explained the change or lack of change in half-life in terms of clearance changes

AGE

Figu re 11-7 The half-life of diazepam increaseswith age from 20 to 80 years (From Rowland ampTozer s Clinical Pharmacokinetics p 230)

Age (y ears)100 20

Half-Life (hrs)

120

40

Here is an interesting change in half-life for diazepam with age Can we explain this in terms of clearance That is does metabolic clearance of diazepam decrease with age

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

In the previous examples we explained the change or lack of change in half-life in terms of clearance changes

AGE

Figu re 11-7 The half-life of diazepam increaseswith age from 20 to 80 years (From Rowland ampTozer s Clinical Pharmacokinetics p 230)

Age (y ears)100 20

Half-Life (hrs)

120

40

Here is an interesting change in half-life for diazepam with age Can we explain this in terms of clearance That is does metabolic clearance of diazepam decrease with age

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

It was then recognized that volume must have increased with age (t12 = Ln 2 x VCL)

It was initially believed that the increase in half-life with increasing age was due to decreased hepatic clearance with age as seen with renal function but measures of

clearance showed no such effect

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

E = mc2

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

VSS = CL bull MRT

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

VSS = CL bull MRT

MRT is Mean Residence Time that has units of time and is a rate constant

that reflects the overall rate of elimination at steady-state for a drug following multiple

compartment kinetics

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

VSS = CL bull MRT Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in

which a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing

MRT or half-life

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

But I have yet to mention the fourth critical pharmacokinetic parameter bioavailability

The organ clearance equation allowed us to

predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through

the liver before reaching the systemic circulation and thus bioavailability can be

low based on first pass hepatic loss in addition to poor absorption

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

CYP3A and P-glycoprotein

(Clin Pharmacol Ther 199558492-7)

(Clin Pharmacol Ther 1992 52453-7)

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

In the early 1990s our group carried out interaction studies in humans with cyclosporine tacrolimus and sirolimus with and without ketoconazole an inhibitor of CYP3A and P-gp as well as with and without rifampin an inducer of CYP3A and P-gp These studies suggest that the major effect of the interaction is on bioavailability as opposed to clearance and that this interaction occurs primarily in the intestine

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

And this then led to development of BDDCS which I presented at the 1st MENA Conference thru BCS

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y Lo

w

Perm

eabi

lity

1 2

3 4

Amidon et al Pharm Res 12 413-420 1995

Carbamazepine Cyclosporine Ketoconazole Tacrolimus

Acetaminophen Propranolol Metoprolol Valproic acid

Acyclovir Cimetidine Ranitidine

Chlorothiazide Furosemide Methotrexate

Biopharmaceutical Classification

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Rat

e

Low

Pe

rmea

bilit

y

Rat

e Class 1 Metabolism

Class 3 Renal amp Biliary Elimination of Unchanged Drug

Class 4 Renal amp Biliary Elimination of Unchanged Drug

Major Routes of Drug Elimination (the very simple discovery)

Class 2 Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Biopharmaceutics Drug Disposition Classification System

BDDCS High Solubility Low Solubility

Exte

nsiv

eM

etab

olis

mPo

or

Met

abol

ism

Class 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and ge70 Metabolism for Biowaiver)

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism

Wu and Benet Pharm Res 22 11-23 (2005)

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way

the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely

eliminated by metabolism (eg diazepam)

What is the Basis for the Discovery The recognition of the correlation between

intestinal permeability rate and extent of metabolism preceded an explanation for these findings That is why should intestinal permeability rate predict the

extent of metabolism

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

High Solubility Low Solubility H

igh

Pe

rmea

bilit

y

Met

abol

ism

Low

Pe

rmea

bilit

y

Met

abol

ism

Class 1 Transporter effects minimal in gut and liver and clinically insignificant

Class 3 Absorptive transporter effects predominate (but can be modulated by efflux transporters)

Class 4 Absorptive and efflux transporter effects could be important

Prediction of Oral Dosing Transporter Effects Based on BDDCS Class

Class 2 Efflux transporter effects predominate in gut but both uptake amp efflux transporters can affect liver

S Shugar ts and L Z Benet Pharm Res 26 2039-2054 (2009)

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug

is minimal

This recommendation comes about based in part on a finding that was

related to the development and characterization of BDDCS

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Another Basic Concept Change Previously it was generally believed that

for drugs excreted primarily by metabolism studies in renal disease patients were unnecessary

Potential inhibition or downregulation of metabolic enzymes by uremic toxins could be tested in vitro

We began to recognize that previously unexplained effects of renal disease on hepatic metabolism can result from accumulation of substances (toxins) in renal failure that modify hepatic uptake and efflux transporters

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Letrsquos return to half-life Clearance is a measure of the bodyrsquos

ability to eliminate a drug

Volume of distribution is a measure of the space available in the body in which

a drug may distribute

Pathology and physiology can change both CL and Vss thereby changing MRT

or half-life Why do we want to know half-life

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Since half-life is a dependent variable that can change as a function of both clearance

a measure of the bodyrsquos ability to eliminate drug and volume of distribution

the space available in the body in which the drug can distribute half-life is

unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

I believe that the only clinically relevant use of half-life is to predict accumulation upon

multiple dosing That is knowing the therapeutically beneficial drug dosing rate

based on clearance and bioavailability what is the appropriate dosing interval to

maximize efficacy and minimize toxicity bull What half-life do we use to make that

calculation bull Irsquove come to realize that none of the

accumulation equations that we now use correctly predict accumulation

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Using Diazepam (Valiumreg) as an Example

Following iv dosing this drug is best described by a 2-compartment body model with half-lives of 132 min

and 297 hr with 954 of the AUC related to the terminal 297 hr half-life We have all been taught that if a half-life

accounts for the great majority of the AUC then this should be the half-life that governs the decision of dosing

interval and prediction of drug accumulation and everyone would predict that a one compartment model

would work for diazepam

Yet the package insert for Valiumreg makes no mention of half-life and the regulatory

approved oral dosing recommendation suggests giving the drug 3-4 times a day

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

The Operational Multiple Dosing Half-Life

A Key to Defining Drug Accumulation in Patients

and to Designing Extended Release Dosage Forms

Selma Sahin and Leslie Z Benet Pharmaceutical Research

25 (12) 2869-2877 (2008)

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

The Operational Multiple Dosing Half-Life (t frac12 op)

When a drug is multiple dosed at time intervals equal to the operational

multiple dosing half-life (τ = t frac12 op) the peak concentration at steady-state will

be double the peak concentration for the first dose and the time course between

Cmaxss and Cminss will be defined by t frac12 op (ie for iv bolus dosing CmaxssCminss = 2)

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

ivbolus 530 hr What are we saying If you dose diazepam ivbolus every 530 hr then Cmaxss will be

twice C maxdose 1 and at steady-state Cmaxss will be twice Cminss

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

You can now understand why the recommended dosing regimen for iv

diazepam is 4-6 times daily

And if you have ever been dosed diazepam iv for severe muscle spasms you know that

the 297 hour half-life has nothing to do with effective relief of the spasms even

though you have been taught that a half-life representing 95 of the AUC is the

relevant half-life So what about oral dosing

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Diazepam (Valiumreg) Following iv dosing this drug is best

described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC

related to the terminal 297 hr half-life t12op

iv 530 hr

t12 abs = 15 min ka=277 hr-1 1295 hr

t12 abs = 22 min ka=192 hr-1 152 hr

t12 abs = 2 hr ka=0347 hr-1 350 hr

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

There are other published methods for calculating accumulation half-

lives In 1985 I proposed that dosing drug every 0693 MRT would result in 2-fold accumulation in the body and dosing every 0693 MRTC would result in 2-fold accumulation

in the plasma (MRTC is mean residence time in the

central compartment = VcCL Note this is not a noncompartmental parameter)

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

And these mean residence time predictions are reasonably close for

iv bolus dosing but completely useless for oral dosing

There is also a parameter designated the ldquoeffective half-liferdquo originally

proposed by Kwan et al (1984) and popularized by Boxenbaum and

Battle (1995) But this parameter also will not predict the values presented earlier for diazepam

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83 Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

What does this mean Letrsquos say you have a new molecular entity whose

terminal half-life in humans is 4 hours the pharmacodynamic effect is related to the systemic concentration time curve and the drug exhibits a

narrow therapeutic index How do you formulate the drug to facilitate twice daily administration

Previously one would attempt to make a zero order release formulation However the data in the previous

slide says that it you slow down the first order absorption half-life to approximate the 4 hour

terminal half you can dose the drug twice a day with a peak to trough ratio of approximately 2

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Letrsquos return to clearance With the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for

uptake and efflux transporters and particularly for transporter-enzyme interplay

One generally unrecognized component of the clearance equations developed in our 1973 paper is

the assumption which is really only explicitly stated in that paper that the partition ratio of free drug between the circulating systemic fluids and

the fluids within an eliminating organ is a constant (usually = 1) Is this true when transporters are

inhibited (or knocked out) or induced

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Although knock-out animals have given us great insight into understanding the importance of a

variety of enzymatic and transporter disposition processes they can not be trusted to provide

quantitative pharmacokinetic characterization of these processes This is particularly true for

evaluating enzyme-transporter interplay In general investigators assume that knocking out

one process does not affect another in terms of quantitative clearance measurements However if

this is not explicitly tested the assumptions are highly questionable especially for transporter-

enzyme interactions In essence CLother must be shown to be constant

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic

clearance measures with the addition of transporters They define

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic

clearances for cellular uptake (influx) and efflux into the systemic circulation respectively

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

CLint = CLintmetab + PSintbile

Now the intrinsic organ clearance (CLintorg) is CLintorg = [PSinf (PSeff + CLint)] CLint

where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux

into the systemic circulation respectively

At the boundary condition where CLint gtgt PSeff ie where the great majority of drug taken up by the hepatocytes is metabolized or excreted

into bile then CLintorg can be approximated by CLintorg cong PSinf

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures

with the addition of transporters They define CLint = CLintmetab + PSintbile

Where do you get CLintmetab from If transporters change the ratio of unbound

concentrations between the liver and the blood which they certainly do transporter

interactions will not only change the PS values but also CLintmetab

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

It is now 42 years since clearance concepts were introduced into pharmacokinetics

The impact has been by 1972 standards unbelievable and clearance has made

pharmacokinetics an important underlying science in drug development selection of dosing regimens

in patients and in the regulatory process As I have tried to point out here the development of clearance volume and half-life and their

application are ongoing and will continue to serve an important role in our scientific understanding of

drug disposition and clinical response

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to

Thank you for your attention

Copy of the slides are available by writing to

LeslieBenetucsfedu

• Basic Concepts They Keep Changing
• Forty-three years ago (1972) the majority of published pharmacokinetic studies were carried out with salicylic acid
• Slide Number 3
• Slide Number 4
• Half-Life observations in 1972 that could not be explained by PK theory then
• Half-Life observations in 1972 that could not be explained by PK theory then
• Slide Number 7
• Slide Number 8
• Slide Number 9
• Slide Number 10
• We described the Extraction Ratio in terms of a ldquowell-stirredrdquo model that weborrowedstole from the Chem Engineers in ldquocrackingrdquo petroleum to make gasoline
• Slide Number 12
• Slide Number 13
• Clearance concepts allowed the field to develop a basic understanding and to make predictions as to how pathological and physiological changes would influence drug kinetics and drug dosing It provided the quantitative rational for Clinical Pharmacology
• Looking at PubMed for the term ldquoDrug Clearancerdquo
• Slide Number 16
• Slide Number 17
• Slide Number 18
• Slide Number 19
• Slide Number 20
• Slide Number 21
• Slide Number 22
• But I have yet to mention the fourth critical pharmacokinetic parameter bioavailabilityThe organ clearance equation allowed us to predict the decrease in bioavailability based on the physiologic phenomenom that orally dosed drugs must pass first through the liver before reaching the systemic circulation and thus bioavailability can be low based on first pass hepatic loss in addition to poor absorption
• Slide Number 24
• Slide Number 25
• Slide Number 26
• Slide Number 27
• Biopharmaceutical Classification
• Major Routes of Drug Elimination(the very simple discovery)
• Slide Number 30
• We now suspect that high permeability rate compounds are readily reabsorbed from the kidney lumen and from the bile facilitating multiple access to the metabolic enzymes In essence the only way the body can eliminate these compounds is via metabolism This would explain why drugs with quite low hepatic clearance are still completely eliminated by metabolism (eg diazepam) aa
• Prediction of Oral Dosing Transporter Effects Based on BDDCS Class
• Recently the FDA has recommended that studies in renal failure patients be carried out even for drugs where renal elimination of unchanged drug is minimal
• Another Basic Concept Change
• Slide Number 35
• Since half-life is a dependent variable that can change as a function of both clearance a measure of the bodyrsquos ability to eliminate drug and volume of distribution the space available in the body in which the drug can distribute half-life is unimportant in defining drug disposition However in using pharmacokinetics as a tool in drug dosing half-life defines the dosing interval and can not be ignored
• I believe that the only clinically relevant use of half-life is to predict accumulation upon multiple dosing That is knowing the therapeutically beneficial drug dosing rate based on clearance and bioavailability what is the appropriate dosing interval to maximize efficacy and minimize toxicity
• Using Diazepam (Valiumreg) as an Example
• The Operational Multiple Dosing Half-Life A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
• The Operational Multiple Dosing Half-Life (t frac12 op)
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 42
• Diazepam (Valiumreg)Following iv dosing this drug is best described by a 2-CBM with half-lives of 132 min and 297 hr with 954 of the AUC related to the terminal 297 hr half-life
• Slide Number 44
• Slide Number 45
• Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation Anita Grover and Leslie Z Benet J Pharmacokinet Pharmacodyn 2011 Jun38(3)369-83Plots of the operational multiple dosing half life to terminal half life ratio vs the terminal half life to absorption half life ratio
• What does this mean
• Letrsquos return to clearanceWith the recognition of the importance of drug transporters during the last decade how do we modify the clearance equations to account for uptake and efflux transporters and particularly for transporter-enzyme interplay
• Although knock-out animals have given us great insight into understanding the importance of a variety of enzymatic and transporter disposition processes they can not be trusted to provide quantitative pharmacokinetic characterization of these processes This is particularly true for evaluating enzyme-transporter interplay
• Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• CLint = CLintmetab + PSintbileNow the intrinsic organ clearance (CLintorg) isCLintorg = [PSinf (PSeff + CLint)] CLint where PSinf and PSeff represent the intrinsic clearances for cellular uptake (influx) and efflux into the systemic circulation respectively
• Letrsquos go back two slides Recently Sugiyama and colleagues have developed a methodology to evaluate hepatic clearance measures with the addition of transporters They define
• It is now 42 years since clearance concepts were introduced into pharmacokinetics
• Thank you for your attentionCopy of the slides are available by writing to