Effect of Ritonavir‐Boosted Danoprevir, a Potent Hepatitis C Virus Protease Inhibitor, on QTc Interval in Healthy Subjects: Results from a Thorough QT Study. Issue 5 (25th March 2013)

• Record Type: Journal Article
• Authors: Morcos, Peter N.; Kulkarni, Rohit; Scoon, Sally; Smith, Patrick F.; Brennan, Barbara J.
• Is Part Of: Drug development research. Volume 74:Issue 5(2013)
• Page Start: 306
• Page End: 315
• Publication Date: 2013-03-25
• Subjects: Drug development -- Periodicals; Drugs -- Research -- Periodicals; 615.19
• DOI: 10.1002/ddr.21080
• Languages: English
• ISSNs: 0272-4391

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <p> <table-wrap position="anchor" orientation="portrait"> <label> <x xml:space="preserve">Table </x> </label> <table border="1"> <colgroup span="1"> <col align="left" span="1" /> </colgroup> <tbody> <tr> <td align="left" rowspan="1" colspan="1">Preclinical Research</td> </tr> </tbody> </table> </table-wrap> </p> <p>Danoprevir is a macrocyclic hepatitis C virus protease inhibitor in clinical development in combination with ritonavir. This study investigated whether ritonavir‐boosted danoprevir (DNVr) affects cardiac repolarization, as measured by study‐specific corrected QT (QTcS) interval. This was a single‐center, single‐dose, randomized, double‐blind, double‐dummy, four‐way crossover study. Healthy subjects received a single dose of each treatment (therapeutic‐dose DNVr 100/100 mg; supratherapeutic‐dose DNVr 400/100 mg; positive control [moxifloxacin 400 mg]; placebo) by randomized sequence, at least 7 days apart. Triplicate readings by continuous Holter 12‐lead digital electrocardiogram (Mortara Instruments, Inc., Milwaukee, WI) were obtained during day 1 and 24 h postdose. There was no clinically relevant increase in QTcS interval with DNVr compared with placebo in 52 subjects. The upper one‐sided 95% confidence interval for placebo‐subtracted change from baseline QTcS was <10 ms at all time points for both DNVr doses. Pronounced increase in QTcS with moxifloxacin treatment confirmed the ECG assay sensitivity. There was no trend for a concentration‐dependent effect of danoprevir on QTcS. DNVr doses were well tolerated. This thorough QTc study demonstrates no clinically or statistically significant effect on cardiac repolarization with administration of a single dose of danoprevir (up to 400 mg) with low‐dose ritonavir (100 mg) in healthy subjects.</p> </abstract>