PII-52
Rimonabant pharmacokinetics in healthy and obese subjects
Abstract
BACKGROUND
Rimonabant is the first selective CB1 blocker developed for the management of multiple cardiometabolic risk factors in overweight/obese patients.
AIMS
To assess the pharmacokinetics (PK) of rimonabant after repeated oral doses in healthy and obese subjects.
METHODS
PK was assessed in healthy young non-obese males in a randomized, double-blind, placebo-controlled, ascending dose study after 3, 10, 20, 40 and 60 mg once-daily doses for 21 days (N=8 active, 2 placebo/group). PK was assessed in young obese subjects (BMI≥<>30 kg/m2) in an open label study after 20 mg once-daily doses for 21 days (N=8/gender). Blood was sampled after the first and last dose for full PK profiles and at pre-dose on specified days. Plasma was analyzed for rimonabant with a validated LC-MS/MS method.
RESULTS
Mean (SD) non-compartmental PK parameters of rimonabant on Day 21 are: (See Table)
| Subjects | Dose (mg) | N | Cmax (ng/mL) | tmaxa (h) | AUC0–24 (ng.h/mL) | t1/2z (h) | tssb (days) |
|---|---|---|---|---|---|---|---|
| Healthy | 3 | 8 | 57.9 (23.1) | 1.51 (1.00, 2.00) | 665 (323) | 210 (132) | |
| Healthy | 10 | 8 | 118 (42.2) | 2.01 (1.50, 3.00) | 1480 (446) | 180 (110) | 12.7 (20.2) |
| Healthy | 20 | 8 | 196 (28.1) | 2.00 (1.50, 6.00) | 2960 (268) | 216 (96.2) | |
| Obese | 20 | 16 | 188 (51.7) | 2.00 (1.00, 4.00) | 2480 (605) | 376 (163) | 25.5 (48.9) |
| Healthy | 40 | 8 | 326 (92.5) | 3.00 (2.00, 5.98) | 4830 (1360) | 193 (73.3) | 12.7 (20.2) |
| Healthy | 60 | 8 | 416 (90.6) | 3.50 (1.50, 6.02) | 6760 (1560) | 151 (59.3) |
- a : median (min, max)
- b : tss=time to reach steady-state, median (90th percentile).
CONCLUSIONS
Rimonabant exhibits no major deviation from dose proportionality up to 20 mg (therapeutic dose range), after which there is a less than dose-proportional increase in exposure. Obese subjects have a longer t1/2z (16 days) than non-obese subjects (6 to 9 days) due to a larger peripheral volume of distribution. Gender has no effect on rimonabant PK.
Clinical Pharmacology & Therapeutics (2005) 79, P50–P50; doi: 10.1016/j.clpt.2005.12.177
