The pharmacokinetics and pharmacokinetic/pharmacodynamic relationships of evacetrapib administered as monotherapy or in combination with statins.
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.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
S
S
Friedrich
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
J J P
JJ
Kastelein
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
D
D
James
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
T
T
Waterhouse
Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, Ohio, USA.
S E
SE
Nissen
South Australian Health & Medical Research Institute, University of Adelaide, Adelaide, Australia.
S J
SJ
Nicholls
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
K A
KA
Krueger