1. Evaluation of the effect of mericitabine at projected therapeutic and supratherapeutic doses on cardiac repolarization in healthy subjects: A thorough QT/QTc study.
- Author
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Chen YC, Haznedar J, Kulkarni R, Vistuer C, Washington C, Liu M, and Smith P
- Subjects
- Action Potentials drug effects, Administration, Oral, Adolescent, Adult, Antiviral Agents adverse effects, Antiviral Agents pharmacokinetics, Arrhythmias, Cardiac diagnosis, Arrhythmias, Cardiac physiopathology, Cross-Over Studies, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Deoxycytidine pharmacokinetics, Double-Blind Method, Electrocardiography, Female, France, Healthy Volunteers, Heart Conduction System physiopathology, Heart Rate drug effects, Hepacivirus drug effects, Hepacivirus enzymology, Humans, Male, Middle Aged, Protease Inhibitors adverse effects, Protease Inhibitors pharmacokinetics, Risk Assessment, Viral Nonstructural Proteins antagonists & inhibitors, Viral Nonstructural Proteins metabolism, Young Adult, Antiviral Agents administration & dosage, Arrhythmias, Cardiac chemically induced, Deoxycytidine analogs & derivatives, Heart Conduction System drug effects, Protease Inhibitors administration & dosage
- 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., (© 2014, The American College of Clinical Pharmacology.)
- Published
- 2014
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