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

center dot Inhibition of cholesteryl ester transfer protein (CETP) is considered a potential new mechanism for the treatment of dyslipidaemia. Whereas several studies have described the effects of the CETP inhibitors, torcetrapib (Pfizer) and dalcetrapib (Roche), on lipids and lipoproteins, few studies have characterized the effect of rising single doses on the pharmacokinetics and pharmacodynamics (CETP activity) of an individual CETP inhibitor or have described the effects of intrinsic and extrinsic factors on the pharmacokinetics and pharmacodynamics of these agents. WHAT THIS STUDY ADDS center dot We have characterized the exposure/response relationship for the inhibition of CETP activity over a wide exposure range. We have shown that single doses of anacetrapib produced marked and dose-dependent inhibition of serum CETP activity with peak effects of similar to 90% inhibition at t(max) and persistent inhibition at 24 h post-dose. We have also shown that whereas food increased exposures to anacetrapib significantly and variably, age, gender and obese status did not meaningfully influence the pharmacokinetics and pharmacodynamics of anacetrapib. 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 similar to 4 h post-dose and an apparent terminal half-life ranging from similar to 9 to 62 h in the fasted state and from similar to 42 to similar to 83 h in the fed state. Plasma AUC and C-max 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 similar to 90% inhibition at t(max) and similar to 58% inhibition at 24 h post-dose. An E-max model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC50 of similar to 22 nm. Food increased exposure to anacetrapib; up to similar to two-three-fold with a low-fat meal and by up to similar 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.