title: Evaluation of the effect of mericitabine at projected therapeutic and supratherapeutic doses on cardiac repolarization in healthy subjects: A thorough QT/QTc study.
abstract: Mericitabine, the di-isobutyl ester prodrug of the cytidine nucleoside analog, is a potent and selective hepatitis C virus NS5B polymerase inhibitor. This thorough QT/QTc study evaluated the effect of mericitabine on cardiac repolarization in healthy subjects. This was a randomized, double-blind, placebo- and active-controlled, 4-way crossover study. A total of 60 subjects were enrolled and randomized to receive a single dose of mericitabine 1,500 mg, 9,000 mg, moxifloxacin 400 mg and placebo in randomly assigned treatment sequences, with at least 14 days between doses. The primary endpoint was the mean difference in baseline-adjusted QT interval using a study-specific correction method (QTcS) between mericitabine and placebo. The upper one-sided 95% confidence interval for the placebo-subtracted change from baseline in QTcS was <10 milliseconds and the mean difference from placebo was <5 milliseconds at all time points for both mericitabine doses. The positive control moxifloxacin caused a pronounced increase in QTcS that peaked 4 hours after oral administration. Furthermore, there was no trend of a concentration-dependent effect of mericitabine on QTcS. In conclusion, mericitabine does not have a clinically or statistically significant effect on cardiac repolarization in healthy subjects at single doses up to 9,000 mg.
authors.affiliation: Roche, Nutley, NJ, USA.
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Haznedar
authors.affiliation: Guardian Analytics, CA, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Kulkarni
authors.affiliation: Roche, Basel, Switzerland.
authors.forename: Christelle
authors.initials: C
authors.lastname: Vistuer
authors.forename: Carla
authors.initials: C
authors.lastname: Washington
authors.affiliation: Roche, Nutley, NJ, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.affiliation: d3 Medicine, Montville, NJ, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D018592:Cross-Over Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D005602:France; D064368:Healthy Volunteers; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018570:Risk Assessment; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D003841:Deoxycytidine; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C552098:2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: clinical trial; electrocardiography; healthy subject; mericitabine; thorough QT/QTc study