basic pharmacokinetics - chapter 15: exams ii

Basic Pharmacokinetics REV. 99.4.25 16-1Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/

CHAPTER 16 Exam 3

Author:Reviewer:

Exam 3


16.1 Pharmacokinetics Final Exam

Summer 1996

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) with antidepressant properties. After oraladministration, the drug is almost completely absorbed from the gastrointestinal tract, however despite completeabsorption, oral bioavailibiliity in man is approximately 50% on account of first-pass hepatic metabolism. Steady-stateplasma concentrations are achieved within 5 to 10 days after initiation of therapy and are 30 to 50 % higher than thosepredicted from single dose data. Fluvoxamine displays non-linear steady state pharmacokinetics over the therapeuticdose range, with disproportionally higher plasma concentrations with higher dosages. Plasma protein binding of flu-voxamine (77%) is low compared with that of other SSRI’s.

V.L. is a 39 year old, 110# female suffering from severe depression. She was admitted to the hospital and pre-scribed 100mg BID of Fluvoxamine but still her depression was uncontrolled at this dose. Her plasma concentrationon this regimen was 20ug/L. After her physician increased her dose to 300 mg BID her plasma concentration was 500ug/L. V.L.’s depression was controlled at this dose, however she was complaining of adverse effects. The therapeuticrange (total drug ug/L) of fluvoxamine is 20-500. Fluvoxamine is metabolized extensively (93%) by the liver to aninactive metabolite.

1. What was her clearance on the 100 mg BID regimen (L/day)?

2. What was her clearance on the 300 mg BID regimen (L/day)?

3. What was her (mg/day)?

4. What was her (mg/L)?

5. The doctor would like to change her therapy in order to minimize side effects. What dose would you

recommend tolower her plasma concentration to 300 ug/L?

V.L. has major complications from a combined hepatitis B infection and cirrhosis of the liver. As a result her

protein binding is reduced to 66%, her changes to 0.03 mg/L and her changes to 100mg/day.

6. What would be her plasma concentration of total fluvoxamine if she maintained the regimen from

question 5 (mg/L)?

7. What is her free plasma concentation (mg/L)?

8. What total fluvoxamine plasma concentration would you recommend achieving to get her free fluvoxa-

mine plasma concentration back to that of the regimen in question 5 (mg/L)?

Vmax

Km

Km Vmax

Exam 3


9. What daily dose of fluvoxamine (by I.V. bolus) would you recommend to get her average free fluvoxamine

plasma concentration approximately back to what it was when she was healthy (mg/day)?

Flurbiprofen is a nonsteroidal anti-inflammatory drug (NSAID) which is a potent inhibitor of prostaglandinsynthesis. It was introduced in the U.S. in 1986 for the treatment of osteoarthritis, rheumatoid arthritis, acute goutyarthritis, and ankylosing spondylitis. Flurbiprofen is stereoselectively and extensively bound to plasma albumin.Approximately 99% of the drug is metabolized by the liver, with trace amounts excreted in the urine as unchangeddrug. Flurbiprofen is 80% bioavailable. The recommended dosages for flurbiprofen are 50 mg q 4-6 hr as needed foranalgesia and 100-300 mg/day for the treatment of inflammatory conditions.

The following healthy and sick parameters are given for the patient V.L., 110# suffering from severe arthritis.Her effective hepatic blood flow is 24 mL/min/kg and effective renal blood flow is 15.0 mL/min/kg. Her healthy half-life is 6 hours. Dr. M. recommends 100 mg flurbiprofen BID.

Healthy Sick

0.15 L/kg 0.19L/kg

% Bound Drug 99.0% 97.0%

10. What is her total body clearance of flurbiprofen (L/hr)?

11. What is the intrinsic hepatic clearance (L/hr)?

12. What is the hepatic extraction ratio?

13. What is the of total flurbiprofen in mg/L?

14. What is the of total flurbiprofen in mg/L?

15. What is the of free flurbiprofen in mic/L?

16. What is the of free flurbiprofen in mic/L?

17. V.L. is now suffering from chronic renal insufficiency. Bound flurbiprofen has now decreased to 97%

due to significant uremia. What is her new hepatic clearance (L/hr)?

18. What is her new k?

19. What is the new N?

20. What would her dose be now, if you wanted to maintain approximately the same free plasma concentra-

tions as the previous therapy with the largest tau?

21. The renal insufficiency clears up and she comes down with mono. Her plasma albumin drops to 50% of

normal thus reducing the bound fraction to 96%. What is her new hepatic clearance using the healthy ?

22. What would her dose be now, if you wanted to maintain approximately the same plasma concentrations as

the previous therapy with the largest tau?

Vd

Cpss

max

Cpss

min

Cpss

max

Cpss

min

Vd

Exam 3


23. The mono clears up, but now there seems to be hepatic stenosis. Her plasma flow is reduced to 50% of

normal. What would her dose be now, if you wanted to maintain approximately the same concentrations

as the previous therapy with the largest tau?

Clentiazem is a chlorinated analog of diltiazem. It is currently undergoing clinical evaluation for the treatmentof angina pectoris and hypertension. The primary mechanism responsible for the antihypertensive effect of CLZ is adecrease in peripheral vascular resistance due to the blockade of calcium channels. The following information wasobtained from a dose of 20 mg Clentiazem given I.V.

24. Can this data be adequately evaluated by a one compartment model?

25. What is the volume of the central compartment (L)?

26. What is the clearance of clentiazem (L/hr)?

27. What is the MRT of clentiazem (hr)?

28. What is the of clentiazem (L)?

29. What is the for clentiazem (L)?

30. What percent of the clentiazem dose is in the central compartment at equilibrium?

Table 2:

A1 37.52ng mL⁄

α 2.70hr1–

B1 16.17ng mL⁄

β 0.078hr1–

k10 0.243hr1–

k12 1.67hr1–

k21 0.868hr1–

AUMC 2729.6ng mL hr2⁄⁄

Vdeff

Vβ

Exam 3


31. What is the , and for a 20 mg IV daily dose clentiazem (ng/mL)?

32. What is the for the above dosing regimen (ng/mL)?

33. What is the for the above dosing regimen (ng/mL)?

Any number from the answer pool may be used once, more than once, or not at all.

TABLE 2-1 Answer Pool

A

B

C

D

E

F

G

H

I

J

A

B

C

D

E

F

G

H

I

J

Cpss

max

Cpss

min

Cpss

avg

basic pharmacokinetics - chapter 15: exams ii

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