Single‐dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects
Authors: Krishna Rajesh , Garg Amit , Panebianco Deborah , Cote Josee , Bergman Arthur J. , Van Hoydonck Pascale , Laethem Tine , Van Dyck Kristien , Chen Jingjing , Chavez‐Eng Cynthia , Archer Laura , Lutz Ryan , Hilliard Deborah , Snyder Karen , Jin Bo , Van Bortel Luc , Lasseter Kenneth C. , Al‐Huniti Nidal , Dykstra Kevin , Gottesdiener Keith , Wagner John A. 
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• 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

• 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 ∼90% inhibition at tmax 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 ∼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.