title: No effect of a single supratherapeutic dose of lersivirine, a next-generation nonnucleoside reverse transcriptase inhibitor, on corrected QT interval in healthy subjects.
abstract: The objective of this study was to investigate the effect of a supratherapeutic dose of lersivirine (LRV) on corrected QT (QTc) interval using Fridericia's equation (QTcF) in healthy subjects. In this randomized, single-dose, placebo- and active-controlled 3-way crossover study, healthy adult males (n = 48) were randomized to receive LRV (2,400 mg), moxifloxacin (400 mg), or placebo for each treatment period. Triplicate 12-lead electrocardiogram measurements were performed, PK samples were collected, and vital signs were measured. Adverse event monitoring and safety laboratory testing were performed. All subjects were white (mean age, 39 years; body mass index [BMI], 25.6 kg/m(2)) and completed the study. Following LRV administration, the upper bound of the 90% confidence interval (CI) for time-matched adjusted mean differences to placebo QTcF at each time point postdose was below the regulatory threshold of 10 ms, satisfying the criteria for a negative thorough QT/QTc study. The highest upper bound of QTcF 90% CI occurred at 6 h for LRV (3.32 ms; 90% CI, 1.47 to 5.17 ms). The study was deemed adequately sensitive as the lower bound of the 90% CI for the adjusted mean QTcF differences between moxifloxacin and placebo at the moxifloxacin historical T(max) of 3 h was >5 ms (15.29 ms; 90% CI, 13.44 to 17.14 ms). There was no statistically significant relationship between LRV exposure and placebo-adjusted change from baseline QTcF or clinically significant changes in QRS complex, pulse rate (PR) interval, heart rate, or blood pressure. LRV (2,400 mg) did not prolong the QTcF interval, and no clinically relevant electrocardiogram or vital sign changes were observed in healthy subjects.
authors.affiliation: Pfizer Global Research and Development, New York, New York, USA. manoli.vourvahis@pfizer.com
authors.forename: Manoli
authors.initials: M
authors.lastname: Vourvahis
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Marie-Noella
authors.initials: MN
authors.lastname: Ndongo
authors.forename: Melissa
authors.initials: M
authors.lastname: O'Gorman
authors.forename: Margaret
authors.initials: M
authors.lastname: Tawadrous
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D001372:Aza Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D024841:Fluoroquinolones; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D009570:Nitriles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010919:Placebos; D011720:Pyrazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011804:Quinolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D009570:Nitriles; D010919:Placebos; D011720:Pyrazoles; D011804:Quinolines; D018894:Reverse Transcriptase Inhibitors; C531151:UK 453,061; D000077266:Moxifloxacin