Abstract Number: 588-P
Authors: JOHN A. WAGNER, XUN CHUN, RONDA K. RIPPLEY, JUTTA L. MILLER, DOMINIQUE BALLAUX, MARINA DE SMET, KEITH M. GOTTESDIENER, BART KEYMEULEN
Institution: Rahway, NJ; Brussels, Belgium
Results: We investigated the pharmacokinetics (PK) and lipid effects of single and multiple doses of MK-0767, a dual PPAR[alpha]/[gamma] agonist, in healthy subjects. The single dose (SD) study was a double-blind, randomized, placebo (PBO)-controlled, alternating 2-panel, rising oral SD protocol; SDs of 1 to 80 mg of MK-0767 were administered. The multiple dose (MD) study was a double-blind, randomized, PBO-controlled, staggered incremental dose, parallel-group protocol; 14-day treatments of daily 0.3 to 25 mg of MK-0767 were administered. For each dose level, 6 subjects received MK-0767 and 2 subjects received PBO. SDs of 1 to 80 mg and MDs of 0.3 to 25 mg of MK-0767 were generally well tolerated. Plasma AUC(0-[infin]) and Cmax increased with SD and MD over the dose ranges studied. The apparent terminal t1/2 averaged ~36 hours following SD and MD. A standard breakfast appeared to affect neither the rate nor extent of absorption of MK-0767 following a single 5-mg dose. Steady state plasma concentrations were achieved following ~8 days of multiple daily dosing. MK-0767 decreased plasma triglycerides (TG) in a dose-dependent fashion after SD and MD administration of MK-0767 compared with PBO (SD, mean maximum TG decrease from baseline 26.2% 24 hr postdose, trend test p<0.001; MD, mean maximum TG decrease from baseline 33.4% 3 hr postdose on day 14 of treatment, trend test p=0.045). MK-0767 decreased plasma FFA in a dose-dependent fashion after SD and MD administration of MK-0767 compared with PBO (SD, mean maximum FFA decrease from baseline 50.4% 24 hr postdose, trend test p<0.001; MD, mean maximum FFA decrease from baseline 66.6% 3 hr postdose on day 14 of treatment, trend test p=0.008). MK-0767 also decreased LDL-cholesterol, total cholesterol, and non-HDL-cholesterol in a dose-dependent fashion after 14 day administration of MK-0767. The SD and MD PK profile of MK-0767 supports once daily dosing. The FFA and lipid effects, even after single doses, suggest that MK-0767 has significant PPAR[alpha]/[gamma] agonist activity in vivo. |
