Single-dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects

Abstract

Aims: Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib. Methods: Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated. Results: Anacetrapib was rapidly absorbed, with peak concentrations occurring at ∼4 h post-dose and an apparent terminal half-life ranging from ∼9 to 62 h in the fasted state and from ∼42 to ∼83 h in the fed state. Plasma AUC and Cmax appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of ∼90% inhibition at tmax and ∼58% inhibition at 24 h post-dose. An Emax model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC50 of ∼22 nm. Food increased exposure to anacetrapib; up to ∼two-three-fold with a low-fat meal and by up to ∼six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure. Conclusions: Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics. © 2009 The British Pharmacological Society.