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PHARMACOKINETICS

[Clinical PK]

V

Dr. Rathnakar U.P.

MD.DIH.PGDHM

Associate Professor

Departments of Pharmacology

Kasturba Medical College

Mangalore

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Target Dose

Treatment No effect or adverse effect

Why? Plasma concn. Less or More

How much to increase or decrease? Is loadingdose required? Clinical pharmacokinetics

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PK Parameters for Target

concn.strategy

Bioavailability- F

Clearance- CL

Volume of dist. aVD

Elimination half life- t

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10 Equations

[1]- t=0.7xV/CL

[2]- Cpss=Dose rate/CL

[3] Dosing rate=Target CpssxCL

[4] Dosing rate=Target CpssxCL/F

[5] Loading dose=targetCpxV/F

[6] Revised dose rate=Previous D.R xTarget

Cpss/Measured Cpss

[7] CL=Rate of elimination/Plasma concn. [8] V=Amount of drug in the body/Plasma

concn.

[9] F= AUC oral/AUC i.v

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2 Equations!

=Rate of elimination

Plasma concn.

=Amount of drug in the body

Plasma concn.

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Bioavailability

Dose

Destroyed

in gut

Not

absorbed

Destroyed

by gut wall

Destroyed

by liver

To

systemic

circulation

Destroyed

in gut

Not

absorbed

Destroyed

by gut wall

Destroyed

by liver

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Bio-availability [F

oral

]

Fraction i.v. = 100% Propranolol95% absorbed Plasma concn-25%-45%

[0.25-0.45] F [Fractional availability]= AUC oral

AUC i.v.

AUC oral

Concn Toxic concn.

Th.Concn.

AUC i.v.

Time30

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V.D

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Drug in beakerDrug + Charcoal in beaker

Concn=20mg/LaVD=10/20mg/L

=0.5L

=Vol.of

beaker

Concn=2mg/L

aVD=10/2mg/L

=5L

=Much more

thanVol.of Beaker

and charcoal

Apparent Volume of Distribution

Vol 0.5L Vol 0.5L

Drug 10mgDrug 10mg

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Distribution. Where do drugs go?

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Volume of distribution

Plasma: 4 liters.

Interstitial volume:

10 liters.

Intracelullar

volume: 28 liters

Relative size of variousdistribution volumes

within

a 70-kg individual

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Blood & Plasma compartment

Vd: around 5 L.

Very high molecular weight

drugs, or drugs that bind to plasma

proteins excesively

Example: Heparin 4L (3-5)

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Extracellular fluid

Vd: between 4 and 14 L.

Drugs that have a low

molecular weight but are

hydrophilic. Example:

Atracuronium 11 L (8-15)

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Vd equal or higher than total body

water

Small water-soluble molecules

Ethanol 38 L (34-41)

Alfentanyl 56 L (35-77)

Drug that binds strongly to tissues.Vd higher than total body water.

Fentanyl: 280 L

Propofol: 560 L

Digoxin:385 L

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Plasma half life [t][Elimination half life]

It is the time required for the plasma conc.of the drug to be reduced to half of itsoriginal [previous] value

Single dose 4-5 t 22

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100

50

150

75

175

87.5

187.5

93.5

193.5

96.5

196.5

98

198

99

199

100

Takes 4-5 half lives to reach steady state concn.

Steady state[Plataeu principle]

Multiple doses

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Target[plasma concn.]level

strategy

Target has to be maintained

1. Effect not quantifiable[antiepileptics]

2. Safety margin is narrow[Digoxin]3. Organ damage

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Drugs with short t1/2

Dose if given [as usually done] at intervals longer than t1/2-

target levels are achieved intermittently

Hours

1 2 34

5 6 7 8 9

Target

80

40

Dose

19

Dr gs ith long t1/2 if the dose req ired to prod ce target

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200 mg

198.5197194

97

199

100

99.2598.5

100100100

Concn

Time

Steady state plasma concn.

Dose is large-toxicity

Small dose-delayed effect

200 mg

100 mg

194 mg

[Loading dose][maintenance doses]

Drugs with long t1/2 if the dose required to produce target

concn is repeated will accumulate and produce toxicity

Hence Loading and maintenance dose strategy

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200 mg

198.5197194

97

199

100

99.2598.5

100100100

Concn

Time


concn is repeated will accumulate and produce toxicity

Hence Loading and maintenance dose strategy

Steady state plasma concn.

200

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Kinetics of Elimination

Clearance

THE CLEARANCE OF A DRUG IS THETHEORETICAL VOLUME OF PLASMAFROM WHICH THE DRUG IS

COMPLETELY REMOVED IN UNIT TIME.

CL=

Rate of elimination

Plasma conc.( C)

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First order[Constant Fraction]

10% of 200mg=20mg

10% of 180mg=18mg

10% of 160mg=16mg

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Pharmacokinetics

10mg

10mg

10mg

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Q. A

Pt. is suffering from acute asthma. What is the 1rate of i.v.infusionand 2loading dose of Theophylline to achieve aTARGET CONCN. OF 10MG./L in a patient Weighing 70kg.?Also calculate the 3maintenance dose by oral route for 48th

hourly,5

12hourly and6

once a dayadministration.What is the 7plasma half life?

Data: 1. CL=2.8L/h/70kg.

2. Foral = 0.96.3. aVD= 35L

4. Target concn=10mg/L

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Half-life

Half life= 0.693xVD/CL

=0.693x35L/70kg2.8L/h/70kg=8.6h

For steady state????= =Data: 1. CL=2.8L/h/70kg.

2. Foral = 0.96.

3. aVD= 35L

4-5 t1/2 36hs

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Calculation Loading dose:

VD= Total amount of drug in the body

Plasma concn.

= Loading dose = VD x Target concn.

= 35L x 10mg/L

=Loading dose= 350mg. Given as bolus i.v

Data:1. CL=2.8L/h/70kg.

2. Foral = 0.96.

3. aVD= 35L

4. Targetconcn.=10mg/L

[Loading dose]

[target concn]

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Calculation: Dosing rate

Maintenance dose

CL = Rate of elimination

Plasma concn.

= Rate of administration! [Dosing rate] =CLxTarget concn

=Dosing rate = 2.8 L/h/70kg x 10mg/L =

= Dosing rate[i.v.infusion]= 28mg/h/70kg man.

Data:1. CL=2.8L/h/70kg.

2. Foral = 0.96.

3. aVD= 35L4. Target concn=10mg/L

[Rate of administration!][Target concn.!]

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Calculation

Divided oral doses:

Dosing rate = 28mg/h = 720mg[Appx]/24h

But F= 0.96

So Oral Dosing rate = i.v dosing rate/ 0.96= 750mg.

= Once a day dose = 750mg,= 8thhourly = 750/3 = 250mg tid

= 12thhourly = 750mg/2 = 350 mg bid.

I.V

8th hourlyOnce a day

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Dosage regimens

Target level strategy: Why?Effect not quantifiable[anti-epileptic, anti-

deppressants]Narrow safety margin[Theophylline, Digoxin] Loading and maintenance dose: Why? Drugs with long t1/2-If the initial dose is large to achieve target

level- subsequent large doses leadaccumulation and toxicity

If small dose are tried takes very long for

the effect 8

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TDM

Monitoring of therapy by measuring plasmaconcn.

Utilizes the principle that the clinical

response of a drug is directly related toits concentration in blood

Monitoring is carried out to support themanagement of patients receivingcertain drugs

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TDM

Monitoring of therapy by measuring plasma concn

Useful

Narrow therapeutic range,

A direct relationship existsbetween the drug levels in plasmaand the pharmacological or toxiceffects,

The therapeutic effect can not bereadily assessed by the clinicalobservation,

Large individual variability in

steady state plasma concentrationexits at any given dose

Appropriate analytic techniquesare available to determine the drugand metabolite levels.

Not useful

Response easily

measurable

Activated in body Hit and run drugs

Irreversible action

Drugs with widetherapeutic range such

as beta blockers and

calcium channel

blockers. 6

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TDM-Indications

1. Low therapeutic index2. Poorly defined clinical end point

3. Non compliance

4. Therapeutic failure5. Drugs with saturable metabolism

6. Wide variation in the metabolism of

drugs7. Major organ failure

8. Prevention of adverse drug effects

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Revised dosing rate

[After TDM]

Expected concn=10mg/l

Measured by TDM=15mg/L

Revised dosing = Previous D.R x Target Cpss

Rate Measured Cpss

750mg/day x 10mg/L = 500mg/day

15mg/L

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Consider liver

and

renal functions

mbbs pk 2014 cl v

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