title: Evacetrapib at a supratherapeutic steady state concentration does not prolong QT in a thorough QT/QTc study in healthy participants.
abstract: OBJECTIVE
  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.
authors.affiliation: 1Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Suico
authors.forename: Stuart
authors.initials: S
authors.lastname: Friedrich
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Krueger
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D019540:Area Under Curve; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015992:Body Mass Index; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D008297:Male; D000077266:Moxifloxacin; D017180:Tachycardia, Ventricular / Q000139:chemically induced
chemical_list: D000900:Anti-Bacterial Agents; D053480:Cholesterol Ester Transfer Proteins; D024841:Fluoroquinolones; D001569:Benzodiazepines; C568301:evacetrapib; D000077266:Moxifloxacin
keywords: QT interval; cholesteryl ester transfer protein; evacetrapib