The Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Relationships of Evacetrapib Administered as Monotherapy or in Combination With Statins

Abstract

Evacetrapib is a novel cholesteryl ester transfer protein (CETP) inhibitor currently being evaluated in a late‐stage cardiovascular outcome trial. Using population‐based models, we analyzed evacetrapib concentration data along with high‐density lipoprotein cholesterol (HDL‐C) and low‐density lipoprotein cholesterol (LDL‐C) data from a 12‐week study in dyslipidemic patients treated with evacetrapib alone or in combination with atorvastatin, simvastatin, or rosuvastatin. Evacetrapib pharmacokinetics were characterized using a two‐compartment model with first‐order absorption. Evacetrapib exposure increased in a less than dose‐proportional manner, similar to other CETP inhibitors. No patient factors had a clinically relevant impact on evacetrapib pharmacokinetics. The relationships between evacetrapib exposure and HDL‐C and LDL‐C were characterized using E max models. The theoretical maximal mean HDL‐C increase and LDL‐C decrease relative to baseline were 177 and 44.1%, respectively. HDL‐C change from baseline was found to be negatively correlated with baseline HDL‐C. A pharmacologically independent LDL‐C reduction was found when evacetrapib was coadministered with statins. CPT Pharmacometrics Syst. Pharmacol . (2014) 3, e94; doi: 10.1038/psp.2013.70 ; published online 22 January 2014