Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults. (24th June 2014)

• Record Type: Journal Article
• Authors: Suico, Jeffrey G; Wang, Ming-Dauh; Friedrich, Stuart; Cannady, Ellen A; Konkoy, Christopher S; Ruotolo, Giacomo; Krueger, Kathryn A
• Is Part Of: Journal of pharmacy and pharmacology. Volume 66:Number 11(2014:Nov.)
• Page Start: 1576
• Page End: 1585
• Publication Date: 2014-06-24
• Subjects: cholesteryl ester transfer protein -- evacetrapib -- high-density lipoprotein -- pharmacodynamic -- pharmacokinetic; Pharmacy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/jphp.12287
• Languages: English
• ISSNs: 0022-3573

Abstract

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.