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: Pharmacy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/jphp.12287
• Languages: English
• ISSNs: 0022-3573

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="jphp12287-sec-0001" sec-type="section"> <title>Objectives</title> <p>We investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of evacetrapib.</p> </sec> <sec id="jphp12287-sec-0002" sec-type="section"> <title>Methods</title> <p>Healthy volunteers received multiple daily doses of evacetrapib (10–600 mg) administered for up to 15 days in a placebo‐controlled study.</p> </sec> <sec id="jphp12287-sec-0003" sec-type="section"> <title>Key findings</title> <p>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.</p> </sec> <sec id="jphp12287-sec-0004" sec-type="section"> <title>Conclusions</title> <p>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.</p> </sec> </abstract>