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J Pharm Pharmacol. 2014 Nov;66(11):1576-85. doi: 10.1111/jphp.12287. Epub 2014 Jun 24.

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

Author information

1
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.

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

PMID:
24961753
PMCID:
PMC4284021
DOI:
10.1111/jphp.12287
[Indexed for MEDLINE]
Free PMC Article

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