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.
RCT Entities:
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.
Entities:
Keywords:
QT interval; cholesteryl ester transfer protein; evacetrapib
Authors: Ellen A Cannady; Ming-Dauh Wang; Stuart Friedrich; Jessica L F Rehmel; Ping Yi; David S Small; Wei Zhang; Jeffrey G Suico Journal: Pharmacol Res Perspect Date: 2015-10-12
Authors: Adam J Nelson; Allan D Sniderman; Marc Ditmarsch; Mary R Dicklin; Stephen J Nicholls; Michael H Davidson; John J P Kastelein Journal: Int J Mol Sci Date: 2022-08-20 Impact factor: 6.208
Authors: Jeffrey G Suico; Ming-Dauh Wang; Stuart Friedrich; Ellen A Cannady; Christopher S Konkoy; Giacomo Ruotolo; Kathryn A Krueger Journal: J Pharm Pharmacol Date: 2014-06-24 Impact factor: 3.765