The pharmacokinetics and pharmacokinetic/pharmacodynamic relationships of evacetrapib administered as monotherapy or in combination with statins

S Friedrich; J J P Kastelein; D James; T Waterhouse; S E Nissen; S J Nicholls; K A Krueger

doi:10.1038/psp.2013.70

The pharmacokinetics and pharmacokinetic/pharmacodynamic relationships of evacetrapib administered as monotherapy or in combination with statins

CPT Pharmacometrics Syst Pharmacol. 2014 Jan 22;3(1):e94. doi: 10.1038/psp.2013.70.

Authors

S Friedrich¹, J J P Kastelein², D James¹, T Waterhouse¹, S E Nissen³, S J Nicholls⁴, K A Krueger¹

Affiliations

¹ Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
² Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
³ Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, Ohio, USA.
⁴ South Australian Health & Medical Research Institute, University of Adelaide, Adelaide, Australia.

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 Emax 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.