Evacetrapib at a Supratherapeutic Steady State Concentration Does Not Prolong QT in a Thorough QT/QTc Study in Healthy Participants. (May 2014)

• Record Type: Journal Article
• Authors: Suico, Jeffrey G.; Friedrich, Stuart; Krueger, Kathryn A.; Zhang, Wei
• Is Part Of: Journal of cardiovascular pharmacology and therapeutics. Volume 19:Number 3(2014:May)
• Page Start: 283
• Page End: 289
• Publication Date: 2014-05
• Subjects: evacetrapib -- QT interval -- cholesteryl ester transfer protein; Cardiovascular pharmacology -- Periodicals; Cardiovascular system -- Diseases -- Treatment -- Periodicals; 616
• DOI: 10.1177/1074248413510784
• Languages: English
• ISSNs: 1074-2484

Abstract

Purpose: To evaluate whether evacetrapib prolongs QT intervals in healthy participants. Methods: This was a single-center, randomized, active and placebo-controlled, 3-period, 6-sequence, and crossover study. Participants were randomized to 1 of 6 treatment sequences in which they received 1 of 3 treatments: evacetrapib 1200 mg daily for 10 days (supratherapeutic dose), moxifloxacin 400 mg for 1 day (positive control), or placebo for 10 days in each of the 3 separate treatment periods. Electrocardiographic parameters were recorded at time points specified in the protocol. The primary end point was the comparison of evacetrapib effect on the population-corrected QT interval (QTcP) to that of placebo at 7 time points following dosing on day 10. An upper limit of the 2-sided 90% confidence interval (CI) <10 milliseconds confirmed the absence of significant effect. Pharmacokinetic parameters were also calculated. Results: Subjects were predominantly male (73.2%) with a mean age of 43.1 years and a mean body mass index of 25.9 kg/m 2 . For the primary analysis, the upper bound of the 2-sided 90% CI for the mean difference between evacetrapib and placebo was <10 milliseconds at all time points on day 10. Following administration of moxifloxacin, the QTcP increased by ≥5 milliseconds at all time points (2, 3, and 4 hours postdose). Maximum plasma concentrations of evacetrapib occurred at a median time of approximately 2 hours, and the mean apparent elimination half-life was approximately 41 hours. The area under the curve and Cmax achieved in this study were both ∼5-fold the values that are expected with the dose level being studied in a phase 3 cardiovascular outcome study. A 1200-mg supratherapeutic dose of evacetrapib was considered to be well tolerated after 10 days of daily dosing in healthy participants. Conclusions: Evacetrapib is not associated with QT interval prolongation, even at supratherapeutic doses.