Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults

Abstract

Objectives: We investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of evacetrapib.

Methods: Healthy volunteers received multiple daily doses of evacetrapib (10-600 mg) administered for up to 15 days in a placebo-controlled study.

Key findings: Mean peak plasma concentrations of evacetrapib occurred at 4-6 h and terminal half-life ranged 24-44 h. Steady state was achieved at approximately 10 days; all subjects had undetectable levels of evacetrapib 3 weeks after their last dose. The trough inhibition of cholesteryl ester transfer protein (CETP) activity was 65 and 84% at 100 and 300 mg, respectively. At the highest dose (600 mg), evacetrapib significantly inhibited CETP activity (91%), increased HDL-C (87%) and apo AI (42%), and decreased LDL-C (29%) and apo B (26%) relative to placebo. For the highest dose tested, levels of evacetrapib, CETP activity, CETP mass, HDL-C and LDL-C returned to levels at or near baseline after a 2-week washout period. Evacetrapib at the highest dose tested did not produce any significant effect on 24-h ambulatory systolic or diastolic blood pressure.

Conclusions: Multiple doses of evacetrapib potently inhibited CETP activity, leading to substantial elevations in HDL-C and lowering of LDL-C. Evacetrapib was devoid of clinically relevant effects on blood pressure and mineralocorticoid levels.

Keywords: cholesteryl ester transfer protein; evacetrapib; high-density lipoprotein; pharmacodynamic; pharmacokinetic.

Figure 1

Plasma concentration (arithmetic means) curve vs time for evacetrapib following first dose (a) and last dose (b) of evacetrapib.

Figure 2

Change in plasma cholesteryl ester transfer protein (CETP) activity (arithmetic means ± standard deviation) following first dose (a) and last dose (b) of evacetrapib.

Figure 3

Relationship between evacetrapib exposure (AUC) and changes from baseline in HDL-C (a) and LDL-C (b) on Day 14 based on observed subject data and E_max model.