A Dual PPAR α/γ Agonist Increases Adiponectin and Improves Plasma Lipid Profiles in Healthy Subjects

Background : The objective of these studies was to evaluate the pharmacokinetics and pharmacodynamics of MK-0767, a prototypical dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist, following administration of single and multiple oral doses in healthy male subjects. Methods : The first study was a double-blind, randomised, placebo-controlled, alternating two-panel, rising dose protocol in which single doses of l–80mg of MK-0767 were administered. The second study was a double-blind, randomised, placebo-controlled, staggered incremental dose, parallel-group protocol in which multiple doses of 0.3–25mg of MK-0767 were administered once daily for 14 days. In both studies at each dose level, six subjects received MK-0767 and two subjects received placebo. Results : Plasma area under the concentration-time curve and maximum plasma concentration increased with single and multiple doses of MK-0767 over the dose ranges studied. The apparent terminal half-life of MK-0767 averaged ≈36 hours following single and multiple doses. Steady-state plasma concentrations were achieved following ≈8 days of multiple doses. Compared with placebo, MK-0767 produced dose-dependent reductions in triglycerides (−26 ± 8% [p = 0.002] and −33 ± 13% [p = 0.008]) and free fatty acids (−50 ± 11% [p < 0.001] and −67 ± 23% [p = 0.008]) following single and multiple doses, respectively. Significant (p < 0.050) dose-dependent alterations in adiponectin (332 ± 36%), low-density lipoprotein cholesterol (−29 ± 5%), total cholesterol (−19 ± 3%), non-high-density lipoprotein cholesterol (−28 ± 4%), and fasting plasma glucose (−6 ± 2%; only in the 25mg group) were observed after multiple doses. Conclusions : The observed effects of MK-0767 on adiponectin, free fatty acids and lipids, even after single doses, demonstrate that this prototypical dual PPAR α/γ agonist has clinically meaningful activity in vivo .