PII-52Rimonabant pharmacokinetics in healthy and obese subjects

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