Article date: October 2009
By: Rajesh Krishna, Amit Garg, Deborah Panebianco, Josee Cote, Arthur J. Bergman, Pascale Van Hoydonck, Tine Laethem, Kristien Van Dyck, Jingjing Chen, Cynthia Chavez‐Eng, Laura Archer, Ryan Lutz, Deborah Hilliard, Karen Snyder, Bo Jin, Luc Van Bortel, Kenneth C. Lasseter, Nidal Al‐Huniti, Kevin Dykstra, Keith Gottesdiener, John A. Wagner, in Volume 68, Issue 4, pages 535-545
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
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.
DOI: 10.1111/j.1365-2125.2009.03465.x
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