dosage regimen (healthy,aged, & diseased patients)

Basic Pharmacokinetics REV. 99.4.25 10-1Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/

CHAPTER 10 Dosage Regimen (Healthy, Aged, and Diseased Patients)

Author: Michael MakoidReviewer: Phillip Vuchetich

OBJECTIVES

1. Given population average patient data, the student will devise (V) dosage regi-mens which will maintain plasma concentrations of drug within the therapeutic range.

2. Given specific patient information, the patient will justify (VI) dosage regimen recommendations.

3. Given patient information regarding organ function, the student will devise (V) and justify (VI) dosage regimen recommendations for the compromised patient.

4. The student will write (V) a professional consult using the above calculations

Dosage Regimen (Healthy, Aged, and Diseased Patients)


10.1 Therapeutic Drug Monitoring

10.1.1 THERAPEUTIC RANGE

The pharmacokinetics of a drug determine the blood concentration achieved froma prescribed dosing regimen. During multiple drug dosing, the blood concentrationwill reflect the drug concentration at the receptor site; and it is the receptor siteconcentration that determines the intensity of the drug’s effect. Therefore, in orderto predict a patient’s response to a drug regimen, both the pharmacokinetics andpharmacological response characteristics of the drug must be understood.

There exists a fundamental relationship between drug pharmacokinetics and phar-macologic response. The relationship between response and ln-concentration issigmoidal. A threshold concentration of drug must be attained befor any responseis ellicited at all. Therapy is accheived when the desired effect is attained becausethe required concentration has been reached. That concentration would set thelower limit of utility of the drug, and is called Effective Concentration (MEC).Most drugs are not “clean”, that is exhibit only the desired therapeutic response.They also exhibit undesired side effects, sometimes called toxic effects at a higher,hopefully a lot higher, concentration. At some concentration, these toxic sideeffects become become intollerable. That concentration, or one below it, wouldset the upper limit of utility for the drug and is called the Maximum TherapeuticConcentration or Minimum Toxic Concentration (MTC). Patient studies havegenerated upper (MTC) and lower (MEC) plasma concentration ranges that aredeemed safe and effective in treating specific disease states. These concentrationsare known as the “therapeutic range” for the drug (see Table 10-1).When a drug isadministered at a fixed dosage to numerous subjects, the blood concentrationsachieved vary greatly due to biological variation. However it is possible to have areasomable

Clinically, digoxin concentrations below 0.8 will elicit a subtherapeuticeffect. Alternatively, when the digoxin concentration exceeds 2.0 sideeffects occur (nausea and vomiting, abdominal pain, visual disturbances). Drugslike digoxin possess a narrow therapeutic index because the concentrations that

ng ml⁄

ng ml⁄



may produce toxic effects are close to those required for therapeutic effects. Theimportance of considering both pharmacokinetics and pharmacodynamics is clear.

Note that drug concentrations may be expressed by a variety of units.

Pharmacokinetic factors that cause variability in plasma drug concentration are:

• Drug-drug interaction

• patient disease state

• physiological states such as age, weight, sex

• drug absorption variation

• differences in the ability of a patient to metabolize and eliminate the drug

If we were to give an identical dose of drug to a large group of patients and thenmeasure the highest plasma drug concentration we would see that due to individualvariability, the resulting plasma drug concentrations differ. This variability can beattributed to factors influencing drug absorption, distribution, metabolism, andexcretion. Therefore, drug dosage regimens must take into account any diseasealtering state or physiological difference in the individual.

Therapeutic drug monitoring optimizes a patient’s drug therapy by determiningplasma drug concentrations to ensure the rapid and safe drug level in the therapeu-tic range.

TABLE 10-1. Average therapeutic drug concentration

DRUG RANGE

digoxin 0.8-2.0

gentamicin 2-10 l

lidocaine 1-4

lithium 0.4-1.4

phenytoin 10-20

phenobarbitol 10-30

procainamide 4-8

quinidine 3-6

theophylline 10-20

ng ml⁄

µg ml⁄

µg ml⁄

mEq L⁄

µg ml⁄

µg ml⁄

µg ml⁄

µg ml⁄

µg ml⁄



Two components make up the process of therapeutic drug monitoring:

• Assays for determination of the drug concentration in plasma

• Interpretation and application of the resulting concentration data to develop a safe and effective drug regimen.

The major potential advantages of therapeutic drug monitoring are the maximiza-tion of therapeutic drug benefits and the minimization of toxic drug effects. Theformulation of drug therapy regimens by therapeutic drug monitoring involves aprocess for reaching dosage decisions.

10.1.2 THERAPEUTIC MONITORING: WHY DO WE CARE?

The usefulness of a drug’s concentration vs. time profile i based on the observation that for many drugs there is a relationship between plasma concentration and ther-apeutic response. There is a drug concentration below which the drug is ineffec-tive, the Minimum Effective Concentration (MEC), and above which the drug has untoward effects, the Minimum Toxic Concentration (MTC). That defines the range in which we must attempt to keep the drug concentration (Therapeutic Range).

The data in Table 10-1 are population averages. Most people respond to drug con-centrations in these ranges. There is always the possibility that the range will bedifferent in an individual patient.

For every pharmacokinetic parameter that we measure, there is a population aver-age and a range. This is normal and is called biological variation. People are differ-ent. In addition to biological variation there is always error in the laboratory assaysthat we use to measure the parameters and error in the time we take the sample.Even with these errors, in many cases, he therapy is better when we attempt tomonitor the patient’s plasma concentration to optimize therapy than if we don’t.This is called therapeutic monitoring. If done properly, the plasma concentrationsare rapidly attained and maintained within the therapeutic range throughout thecourse of therapy. This is not to say all drugs should be monitored. Some drugshave a such a wide therapeutic range or little to no toxic effects that the concentra-tions matter very little. Therapeutic monitoring is useful when:

• a correlation exists between response and concentration

• the drug has a narrow therapeutic range

• the pharmacological response is not easily assessed

• there is a wide inter-subject range in plasma concentrations for a given dose

In this era of DRGs, where reimbursement is no longer tied to cost, therapeuticmonitoring of key drugs can be economically beneficial to an institution. A recentstudy (DeStache 1990) showed a significant difference with regard to days in the



hospital between the patients on gentamicin who were monitored (and their dosageregulated as a consequence) vs. those who were not. With DRGs the hospital wasreimbursed a flat fee irrespective of the number of days the patient stayed in thehospital. If the number of days cost less than what the DRG paid, the hospitalmakes money. If the days cost more than the hospital loses money. This studyshowed that if all patients in the hospital who were on gentamicin were monitored,the hospital would save $4,000,000. That’s right FOUR MILLION per year. Iwould say that would pay my salary, with a little left over, and that is only onedrug!

The process of therapeutic monitoring takes effort.

• First the MD must order the blood assays.

• Second, someone (nurse, med tech, you) must take the blood.

• Someone (lab tech, you) must assay the drug concentration in the blood.

• You must interpret the data

• You must communicate your interpretation and your recommendations for dosage regimen change to the MD. This will allow for informed dosage decisions.

• You must follow through to ensure proper changes have been made.

• You must continue the process throughout therapy. Therapeutic monitoring, in many cases, will be part of your practice. It can be very rewarding

Thus, if we have deterimined the therapeutic range, we could use pharmacokinet-ics to determine the optimum dosage regemin to maintain the patient’s plasma con-centration within that range.

10.1.3 STEADY STATE

It is rare that a drug is given only once. Most therapies consist of multiple dosesof several days duration, if not several years. It is necessary, therefore, to be ableto asess plasma concenterations, both the peak which much be at or below theMTC and the trough which must be at or above the MEC for the drug to be effec-tive under these conditions. Thus when we dose a patient, the concentration pro-file must be within the Therapeutic Range during the entire time that the patient istaking the drug. We can calculate the plasma concentrations in the followin man-ner. In the simplest model, suppose we give a drug by IV Bolus (because the mathis simpler). The equation which would result be

I.V. Bolus Multiple Dose (EQ 10-1)

The peak would be

Cp Cp0 ekt–( ) D

V---- e

kt–( )⋅ =⋅=



(EQ 10-2)

If we allowed the drug to be eliminated for hours, the trough would be:

(EQ 10-3)

Upon giving a second dose, prior to the complete removal by the body of the first

dose the would be the second dose plus what was left from the first dose:

(EQ 10-4)

and the would be times , thus:

: (EQ 10-5)

After n doses, the would be:

(EQ 10-6)

while the would be:

(EQ 10-7)

Subtracting equation 10-7 from equation 10-6 to eliminate the series yields:

(EQ 10-8)

is also which means that

(EQ 10-9)

Equating equation 10-8 and equation 10-9 and solving for yields:

(EQ 10-10)

At large n, and thus the steady state maximum, , is:

Cpmax1 D

V----=

τ

Cpmin1 D

V---- e

k τ⋅( )–( )⋅=

Cpmax2

Cpmax2 D

V---- D

V---- e

k τ⋅( )–( )⋅ +=

Cpmin2

Cpmax2

ek τ⋅( )–( )

Cpmin2 D

V---- e

k τ⋅( )–( )⋅ DV---- e

2k τ⋅( )–( )⋅ +=

Cpmaxn

Cpmaxn D

V---- D

V---- e

k τ⋅( )–( ) … DV---- e

n 1–( )k τ⋅( )–( )⋅+ +⋅+=

Cpminn

Cpminn D

V---- e

k τ⋅( )–( )⋅ DV---- e

2k τ⋅( )–( )⋅ … D

V---- e

nk τ⋅( )–( )⋅+ + +=

Cpmaxn

Cpminn

– DV---- D

V---- e

nk τ⋅( )–( )⋅ D

V---- 1 e

nk τ⋅( )––( )⋅=–=

Cpminn

Cpmaxn

ek τ⋅( )–⋅

Cpmaxn

Cpminn

– Cpmaxn

Cpmaxn

ek τ⋅( )–

Cpmaxn

1 ek τ⋅( )–

–( )=⋅–=

Cpmaxn

Cpmaxn D

V---- 1 e

nk τ⋅( )––

1 ek τ⋅( )–

–----------------------------⋅=

enk τ⋅( )–

0⇒ Cpmaxss



(EQ 10-11)

and the steady state minimum, , is :

(EQ 10-12)

In order to make a general equation set from equation 10-11 and equation 10-12,

let N be the number of half lives in a dosing interval, , and

. Substituting into the function , yields and

thus equation 10-11 becomes:

(EQ 10-13)

and equation 10-12 becomes :

(EQ 10-14)

The average drug concentration under these conditions would be equivalant to thesteady state concentration attained by an infusion of the same rate, i.e. if we wereto give a multiple dose at 200 mg every four hours (q4h) or 400 mg every eighthours (q8h), the average that would be attained would be equivelaent to the steadystate plasma concentration attained by giving an infusion at 50 mg/hr, (Q = 50 mg/

hr), and thus, in the infusion, the and in multiple dosing , and

so:

(EQ 10-15)

Oral Multiple Dosing (Approximation)

Similar equations, although more complex, can be derived for multiple dose oralproducts. However, if we were agreed to live with some error these equations, withsome modifications could be used to approximate multiple dose oral products.

The error on both calculated and would be in the direction of

safety, i.e. the calculated would be higher and the calculated wouldbe lower that their respective multiple dose oral calculations. Thus, if the simpler

Cpmaxss D

V---- 1

1 ek τ⋅( )–

–-------------------------⋅=

Cpminss

Cpminss D

V---- e

k τ⋅( )–

1 ek τ⋅( )–

–-------------------------⋅=

N τt1 2⁄---------=

k 2( )ln( ) t1 2⁄⁄= ek τ⋅( )–

ek τ⋅( )– 1

2---

N=

Cpmaxss D

V---- 1

1 12---

N–

---------------------⋅=

Cpminss D

V----

12---

N

1 12---

N–

---------------------⋅=

Cpss Q

k V⋅----------= Q D

τ----=

k τ⋅ 0.693 N⋅=

Cpss

avg

DV K τ⋅ ⋅------------------- D

V 0.693 N⋅ ⋅------------------------------ 1.443 D⋅

N V⋅----------------------===

Cpmaxss

Cpminss

Cpmaxss

Cpminss



equations place the and within the Therapeutic Range, the oral multi-

ple dose equations would also. The two modifications would be to the Dose. Bio-availability, f, must be considered, and if the drug given is not the drug measured inthe blood, the salt factor, S, the difference in the molecular weight of the two com-

pounds must be taken into account, (i.e. ). Thus, when amino-

phyline, which is a complex consisting of two theophyline molecules and anethylinedyamine molecule is given, but theophyline is measured, the salt factor,

. Thus for oral multiple dose, we can approximate

for

using IV bolus equations as such :

(EQ 10-16)

(EQ 10-17)

(EQ 10-18)

because errors involved with this approximation both in maximum and minimumcalculations (peak and trough) place the drug further within the TherapeuticRange, i.e. the real peaks are lower than the calculated peaks and the real troughsare higher than the calculated troughs, thus both errors are on the side of safety.

Dosing Interval The object of pharmacokinetics is to optimize therapy. By definition, that is tomaintain the plasma concentration of the drug within the therapeutic range for theduration of the therapy presuming that is needed. Thus, the concentrations muststay within the MTC and MEC or

(EQ 10-19)

by deviding equation 10-18 into equation 10-16 and simplifying. Given these lim-its, the maximum dosing interval, , is obtained by solving for Nmax:

Cpmaxss

Cminss

SMWmeasured

MWgiven-------------------------------=

SMWTheo

MWAmino------------------------ 2 180.17⋅

420.44------------------------ 0.857===

Cpmaxss S f D⋅ ⋅

V------------------ 1

1 12---

N–

---------------------⋅=

Cpss

avg

S f D⋅ ⋅V K τ⋅ ⋅------------------- S f D⋅ ⋅

V 0.693 N⋅ ⋅------------------------------ 1.443 S f D⋅ ⋅ ⋅

N V⋅------------------------------------===

Cpminss S f D⋅ ⋅

V------------------

12---

N

1 12---

N–

---------------------⋅=

MTCMEC-------------

Cpmaxss

Cpminss

------------------- 2Nmax==

τmax



(EQ 10-20)

and since by definition,

(EQ 10-21)

is not necessarily the dosing interval of choice, but it is the maximum dosinginterval attainable without sustained or controlled release delivery systems.

Accepable dosing intervals are those which result in a dose being given at the sametime of the day, every day. Imagine, if you will, the chaos on the nursing floor ifthe dose for a given drug were every 15 hours. Compliance, none too high whenthe patient is given a reasonable dosing interval, would go straight to the toilet ifwe asked the patient to take a tablet every 5.3 hours. What would be optimal wouldbe to tie the takeing of the drug with an activity that occurs the same time everyday for once a day therapy, or at least dose the same time every day. Thus, formultiple daily doses, the only regimens that work are those which when devideinto 24 hours give unit answers: QD = 24/1 = q24h; BID = 24/2 = q12h, TID = 24/3 = q8h; QID = 24/4 = q6h; q4h; q3h; q2h. These result in decreasing orders ofpatient compliance (unless the patient is really motivated to take the drug every 2hours - forget it.) Thus the maximum acceptable dosing interval would be the larg-est acceptable dosing interval below the . So, for example if is 15.7hours, the maximum acceptable dosing interval would be 12 hours. we could alsodose every 8, 6 or 4 hours if necessary.

Nmax

Ln MTCMEC-------------

Ln2--------------------------=

Nmax

τmax

t1 2⁄-----------=

τmax Nmax t1 2⁄⋅=

τmax

τmax τmax



10.2 Diseases - Dosing the Compromised Patient

As previously discussed in the chapter on clearance, diseases result in changes in clearance. These are routinely as a consequence of changes in organ function or blood flow to the organ. Diseases which cause a change in clearance, do so by changing either the elimination rate constant, K, or the volume of distribution, Vd, or both. Thus the fractional change in total body clearance :

(EQ 10-22)

Where X* indicates new or changed variable. In general, if ,

changes in dosage regimen are not necessary. In order to return a previously con-trolled healthy pateint back to the therapeutic range, a general rule of thumb is sug-gested as an initial starting point. The desease modifies K (as t1/2) and V. As

pharmacists, we can modify D and . These variables are paired in the above

equations (equation 10-16 and equation 10-18), D with V (in ) and

with (in ). If the physiological change is a change in V, the pharmacist

would recommend a change in D proportionally, and if the half life changes, thepharmacist would recommend a change in the dosing interval proportionally.Remenber, the object is to get the plasma concentrations back to where they wereprior to the illness. The only problem is that we are limited to these recommendedchanges being incremental and not continuous. That is a change in dose is limitedto the available dosage forms and strengths and a change in dosing interval islimeted to the accepatable dosing interval.

Protein Binding If the drug is highly protein bound, the object would be to get the free concentra-tion back to what it was prior to illness. Consequently, equation 10-16, equation10-17, and equation 10-18 would be rewritten thus:

(EQ 10-23)

(EQ 10-24)

FCltot

Cltot∗

Cltot

-------------- K∗ V∗⋅K V⋅

------------------==

0.80 FCl tot1.2< <

τS f D⋅ ⋅

V------------------ t1 2⁄

τ N τt1 2⁄---------=

Cpss

maxfree

fu Cpss

max⋅

fu S f D⋅ ⋅ ⋅V

-------------------------- 1

1 12---

N–

--------------------⋅= =

Cpss

avgfree

fu C⋅= pss

avg

fu S f D⋅ ⋅ ⋅V K τ⋅ ⋅

--------------------------fu S f D⋅ ⋅ ⋅

V 0.693 N⋅ ⋅------------------------------==



(EQ 10-25)

Some interesting and unexpected things result from these relationships. Sinceplasma or blood concentrations are usually measured, if a drug is highly proteinbound and the desease results in upsetting that equilibrium, you might see toxicityresulltling from normal or even subtherapeutic measured concentrations. More onthat in the chapter on protein binding.

Cpss

min free

fu C⋅ pss

min

fu S f D⋅ ⋅ ⋅V

--------------------------

12---

N

1 12---

N–

--------------------⋅= =



10.3 Problems



Alprazolam (Problem 10 - 1)

Juhl, R. et al., "Alprazolam pharmacokinetics in alcoholic liver disease", Journal of Clinical Pharmacology, Vol.24, (1984), p. 113 - 119.

Alprazolam is an anti-anxiety agent which is metabolized to 4-hydroxy and α-hydroxy metabolites. In thisstudy, patients with cirrhosis of the liver and healthy patients were each given doses of 1.0 mg of Alpra-zolam. The following data is for healthy patients.

Assume that your patient weighs 70 kg when answering the following:

1. Find k.

2. Find the MRT.

3. Find the .

4. Find the AUMC.

5. Find τ.

6. What is N?

7. What is the patient's maximum plasma concentration, , under this dosage regimen.

8. What is the patient's average plasma concentration, , under this dosage regimen.

9. What is the patient's minimum plasma concentration, , under this dosage regimen.

Problem Submitted By: Maya Leicht AHFS 00:00.00Problem Reviewed By: Vicki Long GPI: 0000000000

PROBLEM TABLE 10 - 1. Alprazolam

Dose 1.0 mg BID

1.16 L/kg

1.22

AUC

529.3



Cefixime (Problem 10 - 2)

Faulkner, R. et al., "Pharmacokinetics of cefixime after once-a-day and twice-a-day dosing to steady state", Journal of Clinical Pharmacology, Vol.27, (1987), p. 807 - 812.

Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram negative bac-teria. In this study, patients received a 200 mg oral dose of cefixime twice daily.

1. Find k.

2. Find MRT.

3. Find Cl.

4. Find the .

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 2. Cefixime

Dose 200 mg BID

3.3 hours

286

32

AUC 14.12



Cefpodoxime (Problem 10 - 3)

Borin, M. et. al., "Pharmacokinetics and tolerance studies of cepodoxime after single-and multiple-dose oral administration of cef-podoxime proxetil", Journal of Clinical Pharmacology, Vol.31, (1991), p. 1137 - 1145.

Cefpodoxime proxetil is a third-generation, broad-spectrum cephalosporin which is given by the oral route. It is a pro-drug which is converted in vivo to cefpodoxime which inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins.

1. Find k.

2. Find MRT.

3. Find Cl.

4. Find the .

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 3. Cefpodoxime

Dose 100 mg BID

2.1 hours

271

79.1

AUC 6.9



Cefprozil (Problem 10 - 4)

Lode, H. et. al., "Multiple-dose pharmacokinetics of cefprozil and its impact on intestinal flora of volunteers", Antimicrobial Agents and Chemotherapy, Vol.36, (1992), p. 144 - 149.

Cefprozil is a broad-spectrum cephalosporin which is given by the oral route. In this study subjects received 500 mgdoses of cefprozil every twelve hours for eight days.

1. Find k.

2. Find MRT.

3. Find Cl.

4. Find the .

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 4. Cefprozil

Dose 500 mg q. 12 hours

55.11minutes

310.25

277.50

AUC 27.80



Clobazam (Problem 10 - 5)

Greenblatt, D. et. al., "Reduced single-dose clearance of clobazam in elderly men predicts increased multiple-dose accumulation", Clinical Pharmacokinetics, Vol.8, (1983), p. 83 - 94.

Clobazam is an agent used in the treatment of anxiety. In this study, patients received 10 mg dose of clobazam daily.

1. Find k.

2. Find MRT.

3. Find the ?

4. Find the AUMC.

5. Find τ.

6. What is N?




10. Your patients renal function drops to 50% of normal. What would be a new dosing regimen under these condi-tions? (Assume that you want to keep < 110% of the normal and that you want to keep > 90% of the normal .)


PROBLEM TABLE 10 - 5. Clobazam

Dose 10 mg daily

180 hours

AUC



Maloprim (Problem 10 - 6)

Edstein, M., Rieckmann, K., and Veenendaal, J., "Multiple-dose pharmacokinetics and in vitro antimalarial activity of dapsone plus pyrimethamine (Maloprim) in man", British Journal of Clinical Pharmacokinetics, Vol.30, (1990), p.259 - 265.

Maloprim is an agent which contains both dapsone and pyrimethamine. In this study, healthy volunteerswere given 100 mg of dapsone plus 12.5 mg pyrimethamine weekly. The following data is for dapsone:

1. Find k.

2. Find MRT.

3. Find Cl.

4. Find the .

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 6. Maloprim

Dose 100 mg weekly

22.6 hours

AUC 35.0



Doxycycline (Problem 10 - 7)

Shmuklarsky, M. et. al., "Failure of doxycycline as a causal prophylactic agent against Plasmodium falciparum malaria in healthy nonimmune volunteers", Annals of Internal Medicine, Vol.120, (1994), p. 294 - 298.

Doxycycline is an antibiotic which has been recommended for prevention of malaria in people traveling to areasendemic to chloroquine-resistant P. falciparum malaria who are unable to take mefloquine. This study determined thatdoxycycline is not effective for this use. Volunteers were given 100 mg doses of doxycycline daily for 10 days.

1. Find k.

2. Find MRT.

3. Find Cl.

4. Find the .

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 7. Doxycycline

Dose 100 mg daily

21.9 hours

AUC 40.7



DQ-2556 (Problem 10 - 8)

Nakashima, M. et. al., "Phase I study of DQ-2556, a new parenteral 3-quaternary ammonium cephalosporin antibiotic", Journal of Clinical Pharmacology, Vol.33, (1993), p. 57 - 62.

DQ-2556 is a new broad-spectrum cephalosporin which is active against many bacteria including Pseudomonas aerug-inosa. Subjects in this study were each given a 2000 mg infusion of DQ-2556 over 5 minutes every 12 hours for a totalof 9 doses.

1. Find Cl.

2. Find k.

3. Find the MRT.

4. Find the .

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 8. DQ-2556

Dose 2000 mg infusion over 5 minutes

17.6 L

8.5

7.1

AUC 241.0



Erythropoetin (Problem 10 - 9)

Gladziwa, U., et al., "Pharmacokinetics of epoetin (recombinant human erythropoietin) after long term therapy in patients under-going haemodialysis and haemofiltration", Clinical Pharmacokinetics, Vol.8, (1983), p. 83 - 94.

Erythropoetin is a regulatory hormone of red blood cells. In this study patients with end-stage renal disease were given150 U/kg of epoetin three times a week.

Assuming that your patient weighs 65 kg, please determine the following:

1. Find k.

2. Find MRT.

3. Find the .

4. Find the AUC.

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 9. Glipizide

Dose 150 U/kg t.i.w.

7.7hours

Cl 5.4



Flecainide (Problem 10 - 10)

Forland, S. et al., "Flecainide pharmacokinetics after multiple-dosing in patients with impaired renal function", Journal of Clinical Pharmacology, Vol.28, (1988), p. 727 - 735.

Flecainide acetate is a class 1C anti-arrhythmic agent which is used in the treatment of ventricular and supraventriculararrhythmias. In this study, subjects were given doses of 100mg of flecainide orally twice daily.

Assume that your patient weighs 70 kg when calculating the following:

1. Find Cl.

2. Find k.

3. Find the MRT.

4. Find the .

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 10. Flecainide

Dose 100 mg BID

7.4 L/kg

486

89

AUC 3.429



Glipizide (Problem 10 - 11)

Kradjan, W. et al., "Glipizide pharmacokinetics: effects of age, diabetes, and multiple dosing", Journal of Clinical Pharmacology, Vol.29, (1989), p. 1121 - 1127.

Glipizide is a second-generation oral hypoglycemic agent used in the treatment of non-insulin-dependent (type II) dia-betes. In this study, both diabetic and non-diabetic elderly men were each given doses of 2.5 mg of glipizide daily forfive days. The data for the non-diabetic group is given below.

1. Find k.

2. Find MRT.

3. Find Cl.

4. Find the .

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 11.

Dose 2.5 mg daily

4.0 hours

0.47

AUC 2325.4



Lomefloxacin (Problem 10 - 12)

Hunt, T. and Adams, M., "Pharmacokinetics and safety of lomefloxacin following multiple doses", Diagn Microbiol Infect Dis, Vol.12, (1989), p. 181 - 187.

Lomefloxacin is a quinolone antibiotic which is useful against both Gram-positive and Gram-negative bacteria. It isused in the treatment of urinary tract infections and lower respiratory tract infections. A dose of 400 mg of lomefloxa-cin was given twice daily to healthy patients.

1. Find k.

2. Find MRT.

3. Find Cl.

4. Find the .

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 12. Lomefloxacin

Dose 400 mg BID

7.32 hours

AUC 61.67



Loratadine (Problem 10 - 13)

Radwanski, E. et al., "Loratadine: multiple-dose pharmacokinetics", Journal of Clinical Pharmacology, Vol.27, (1987), p. 530 - 533.

Loratadine is an antihistamine which is orally active. In this study, healthy, male volunteers were each given a 40-mgloratadine capsule daily for ten days.

1. Find k.

2. Find MRT.

3. Find Cl.

4. Find the .

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 13. Loratadine

Dose 40 mg daily

14.4 hours

AUC 96.0



Methamphetamine (Problem 10 - 14)

Cook, C., et al., "Pharmacokinetics of oral methamphetamine and effects of repeated daily dosing in humans", Drug Metabolism and Disposition, Vol.20, (1992), p. 856 - 861.

Methamphetamine is a CNS stimulant which is used in the treatment of attention deficit disorder and obesity. In thisstudy, subjects were given a 0.125 mg/kg dose of methamphetamine daily.

Assume that your patient weighs 70 kg when calculating the following:

1. Find k.

2. Find MRT.

3. Find the .

4. Find the AUC.

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 14. Methamphetamine

Dose 0.125 mg/kg daily

8.46 hours

65.0

212



Mexiletine (Problem 10 - 15)

Gillis, A. and Kates, R., "Clinical pharmacokinetics of the newer antiarrhythmic agents", Clinical Pharmacokinetics, Vol.9, (1984), p. 375 - 403.

Mexiletine is a class Ib antiarrhythmic agent. In this study, volunteers each received a 1600 mg dose orally each day.

1. Find k.

2. Find the MRT.

3. Find the .

4. Find the AUC.

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 15. Mexiletine

Dose 1600 mg daily

380 L

681



Moxisylyte (Problem 10 - 16)

Costa, P. et al., "Multiple-dose pharmacokinetics of moxisylyte after oral administration to healthy volunteers", Journal of Phar-maceutical Sciences, Vol.82, (1993), p. 968 - 971.

Moxisylyte is an α-adrenergic blocker which has been used in Europe for some times as a vasodilator in thetreatment of such disease states as age-associated mental impairment, acrocyanosis, Raynaud's syn-drome, vascular cochlearvestibular disorders, glaucoma, and benign prostatic hyperplasia.

1. Find k.

2. Find MRT.

3. Find Cl.

4. Find the .

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 16. Moxisylyte

Dose 240 mg BID

2.28 hours

AUC 11186



Naproxen (Problem 10 - 17)

Ouweland, F. et. al., "Hypoalbuminaemia and naproxen pharmacokinetics in a patient with rheumatoid arthritis", Clinical Phar-macokinetics, Vol.11, (1986), p. 511 - 515.

The pharmacokinetics parameters of naproxen were looked at in patients with rheumatoid arthritis in this study. Apatient received a dose of 500 mg of naproxen orally twice daily.

1. Find Cl.

2. Find k.

3. Find the MRT.

4. Find the .

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 17. Naproxen

Dose 500 mg BID

9.0 L

AUC 1134



Nisoldipine (Problem 10 - 18)

Harten, J. et al., "Influence of renal function on the pharmacokinetics and cardiovascular effects of nisoldipine after single and multiple dosing", Clinical Pharmacokinetics, Vol.16, (1989), p. 55 - 64.

Nisoldipine is a second-generation calcium-channel blocker which is under investigation for use as an anti-hyperten-sive agent. Nisoldipine is mainly eliminated through liver metabolism with metabolites being excreted mainly in theurine but also in the feces. The systemic clearance of nisoldipine depends greatly on liver blood flow.

1. Find k.

2. Find MRT.

3. Find Cl.

4. Find the ?

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 18. Nisoldipine

Dose 10 mg BID orally

7.9 hours

AUC 5.2



Pefloxacin (Problem 10 - 19)

Bruno, D. et al., "Bayesian versus NONMEM estimation", , Vol. , (19 ), p. 657 - 668.

Pefloxacin is an antibiotic used to treat patients who are in the intensive care unit. For this study, patients were given a400 mg dose of pefloxacin twice daily for eight days.

1. Find k.

2. Find MRT.

3. Find the ?

4. Find the AUC.

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 19. Pefloxacin

Dose 400 mg BID

21.3 hours

Cl 3.77



Phenylpropanolamine (Problem 10 - 20)

Scherzinger, S., Rowse, R., and Kanfer, I., "Steady state pharmacokinetics and dose-proportionality of phenylpropanolamine in healthy subjects", Journal of Clinical Pharmacology, Vol.30, (1990), p. 372 - 377.

Phenylpropanolamine is a sympathomimetic agent which is used both for its action as a nasal decongestant and itsaction as an anorexiant. In this study healthy volunteers were given doses of 25 mg every four hours for a total ofseven doses. It was found that phenylpropanolamine is 77% renally excreted.

1. Find k.

2. Find MRT.

3. Find Cl.

4. Find the AUC.

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 20. Phenylpropanolamine

Dose 25 mg q. 4 hours

4.71 hours

4.08 L/kg

0.5



Promethazine (Problem 10 - 21)

Taylor, G. and Houston, J., "Changes in the disposition of promethazine during multiple dosing in rabbits", Journal of Clinical Pharmacology, Vol.37, (1985), p. 243 - 247.

Promethazine is an agent used as an anti-histamine and a sedative. In this study rabbits weighing 2.7 to 3.3 kilogramseach received a 10 mg/kg dose of promethazine every 24 hours for 14 days.

1. Find k.

2. Find MRT.

3. Find the ?

4. Find the AUC.

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 21. Promethazine

Dose 10 mg/kg

249 minutes

65.0



Rufloxacin (Problem 10 - 22)

Mattina, R. et al., "Pharmacokinetics of rufloxacin in healthy volunteers after repeated oral doses", Chemotherapy, Vol.37, (1991), p. 389 - 397.

Rufloxacin is a broad-spectrum, fluoroquinolone antibiotic. In this study a patient was given a loading dose of 300 mgof rufloxacin followed by 150 mg of rufloxacin daily for five days.

1. Find k.

2. Find the MRT.

3. Find the .

4. Find the AUMC.

5. Find τ.

6. What is N?





PROBLEM TABLE 10 - 22. Rufloxacin

Dose 150 mg daily

104 L

41

10

AUC 121.5



Velnacrine (HP 029) (Problem 10 - 23)

Puri, S. et al., "Multiple dose pharmacokinetics, safety, and tolerance of velnacrine (HP 029) in healthy elderly subjects: a poten-tial therapeutic agent for Alzheimer's disease", Journal of Clinical Pharmacology, Vol.30, (1990), p. 948 - 955.

Velnacrine is an investigative agent which has central cholinergic action and may be beneficial in the treatment ofAlzheimer's disease. Healthy, elderly, men were given doses of 100 mg twice daily in this study. It was found that 30%of the velnacrine dose was excreted unchanged.

1. Find k.

2. Find the MRT.

3. Find Cl.

4. Find the .

5. Find the AUMC.

6. Find τ.

7. What is N?





PROBLEM TABLE 10 - 23. Velnacrine (HP 029)

Dose 100 mg BID

2.4 hours

AUC 809.5



10.4 Answers

Alprazolam

1. 0.0631 h-1

2. 15.85 hours

3. 10.98 hours

4. 8387.81

5. 12

6. 1.093

7. 23.19

8. 16.26

9. 10.876

Cefixime

1. 0.210 h-1

2. 4.76 hours

3. 14.164 L/h

4. 67.435 L

5. 62.224

6. 12

7. 3.64

8. 3.225

9. 1.177

10. 0.259

Cefpodoxime

1. 0.330 h-1

2. 3.03 hours

3. 14.49 L/h

4. 43.91 L

5. 20.905



6. 12

7. 5.714

8. 2.322

9. 0.575

10. 0.0442

Cefprozil

1. 0.0126 min-1

2. 76.51 minutes

3. 17.99 L/h

4. 23.83 L

5. 36.84

6. 12

7. 13.065

8. 20.98

9. 2.317

10. 2.45

Maloprim

1. 0.0307 h-1

2. 32.6 hours

3. 2.857 L/h

4. 93.16 L

5. 1141.17

6. 168

7. 7.435

8. 1.08

9. 0.208

10. 6.25

Doxycycline

1. 0.0317 h-1



2. 31.595 hours

3. 2.457 L/h

4. 77.629 L

5. 1285.92

6. 24

7. 1.096

8. 2.42

9. 1.696

10. 1.133

DQ-2556

1. 8.299 L/h

2. 0.4715 h-1

3. 2.12 hours

4. 1.47 hours

5. 511.11

6. 12

7. 8.163

8. 114

9. 20.083

10. 0.398

Erythropoetin

1. 0.09 h-1

2. 11.11 hours

3. 3599.24 mL

4. 30092.6

5. 334291.14

6. 72

7. 9.35

8. 2713.24



9. 417.98

10. 4.156

Glipizide

1. 0.173 h-1

2. 5.77 hours

3. 1.075 L/h

4. 6.204 L

5. 13419.37

6. 24

7. 6

8. 0.4094

9. 96.893

10. 6.396

Flecainide

1. 29.16 L/h

2. 0.0563 h-1

3. 17.76 hours

4. 12.31 hours

5. 60.91

6. 12

7. 0.975

8. 0.393

9. 0.286

10. 0.200

Lomefloxacin

1. 0.0947 h-1

2. 10.56 hours

3. 6.486 L/h

4. 68.497 L



5. 651.27

6. 12

7. 1.639

8. 8.6

9. 5.139

10. 2.76

Loratadine

1. 0.0481 h-1

2. 20.77 hours

3. 416.67 L/h

4. 8656.17 L

5. 1994.38

6. 24

7. 1.67

8. 6.746

9. 4

10. 2.125

Methamphetamine

1. 0.082 h-1

2. 12.21 hours

3. 46.7 L

4. 2.244

5. 27.383

6. 24

7. 2.837

8. 213.74

9. 93.48

10. 29

Moxisylyte



1. 0.304 h-1

2. 3.29 hours

3. 0.0215 L/h

4. 70.574 mL

5. 36794.61

6. 12

7. 5.263

8. 3.492

9. 0.9322

10. 0.0909

Naproxen

1. 0.441 L/h

2. 0.049 h-1

3. 20.412 hours

4. 14.149 hours

5. 23147.21

6. 12

7. 0.848

8. 124.98

9. 94.5

10. 69.43

Mexiletine

1. 0.1075 h-1

2. 9.3 hours

3. 6.45 hours

4. 39.16

5. 364.17

6. 24

7. 3.723



8. 4.256

9. 1.632

10. 0.345

Nisoldipine

1. 0.0877 h-1

2. 11.397 hours

3. 1923.08 L/h

4. 21.92 mL

5. 59.27

6. 12

7. 1.52

8. 700.7

9. 433.3

10. 244.5

Pefloxacin

1. 0.0325 h-1

2. 30.73 hours

3. 115.85 L

4. 106.1

5. 3260.4

6. 12

7. 0.563

8. 10.68

9. 8.84

10. 7.23

Phenylpropanolamine

1. 0.147 h-1

2. 6.795 hours

3. 36.03 L/h



4. 0.694

5. 4.715

6. 4

7. 0.849

8. 229.5

9. 173.5

10. 127.4

Promethazine

1. 0.167 h-1

2. 5.987 hours

3. 70.05 L

4. 2.56

5. 15.35

6. 24

7. 5.78

8. 436.19

9. 106.84

10. 7.92

Rufloxacin

0.0237 h-1

42.28 hours

29.30 hours

5136.6

24

0.819

3.33

2.54

1.89

Velnacrine



1. 0.289 h-1

2. 3.462 hours

3. 123.53 L/h

4. 427.73 L

5. 2802.87

6. 12

7. 5

8. 241.33

9. 67.46

10. 7.54

dosage regimen (healthy,aged, & diseased patients)

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