Effect of Ritonavir-Boosted Danoprevir, a Potent Hepatitis C Virus Protease Inhibitor, on QTc Interval in Healthy Subjects: Results from a Thorough QT Study

Authors

  • Peter N. Morcos,

    Corresponding author
    • Pharma Research and Early Development, Department of Clinical Pharmacology, Hoffmann–La Roche Inc., Nutley, NJ, USA
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  • Rohit Kulkarni,

    1. Department of Biostatistics, Genentech, South San Francisco, CA, USA
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  • Sally Scoon,

    1. Pharma Research and Early Development, Clinical Programme and Study Management, Roche Products Ltd, Welwyn Garden City, UK
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  • Patrick F. Smith,

    1. Pharma Research and Early Development, Department of Clinical Pharmacology, Hoffmann–La Roche Inc., Nutley, NJ, USA
    Current affiliation:
    1. d3 Medicine, Montville, NJ, USA
    2. University at Buffalo, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA
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  • Barbara J. Brennan

    1. Pharma Research and Early Development, Department of Clinical Pharmacology, Hoffmann–La Roche Inc., Nutley, NJ, USA
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  • All authors were employees of Roche at the time of the study. No authors have Conflicts of Interest information to declare.
  • Additional Supporting Information can be found in the online version of this article.

Correspondence to: Peter N. Morcos, Department of Clinical Pharmacology, Roche, 340 Kingsland Street. Nutley, NJ 07110, USA.

E-mail: peter.morcos@roche.com

Abstract

Preclinical Research

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.

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