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Characterization of the Transmembrane Transport and Absolute Bioavailability of the HCV Protease Inhibitor Danoprevir

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Abstract

Background and Objectives

Understanding transmembrane transport provides a more complete understanding of the pharmacokinetics of a drug and mechanistic explanations for drug–drug interactions. Here, the transmembrane transport of danoprevir (hepatitis C virus protease inhibitor) and the effects of ritonavir and ciclosporin on transmembrane transport of danoprevir were evaluated and clinical pharmacokinetic studies of danoprevir co-administered with/without ritonavir and ciclosporin were conducted.

Methods

Transcellular transport of danoprevir was evaluated in Lewis lung cancer porcine kidney, Madin-Darby canine kidney, or Chinese hamster ovary cells transfected with human transport proteins, and in human hepatocytes. The pharmacokinetics of intravenous and oral danoprevir administered with/without ritonavir, and the impact of ciclosporin on danoprevir pharmacokinetics were evaluated in randomized, open-label, crossover studies in healthy subjects.

Results

Danoprevir transport in vitro involved organic anion transporting polypeptide (OATP) 1B1, OATP1B3, P-glycoprotein, and multidrug resistance protein-2, but not breast cancer resistance protein. Ritonavir and ciclosporin inhibited transport of danoprevir by human hepatocytes. The pharmacokinetics of intravenous danoprevir 6 mg were not altered by oral ritonavir 100 mg. In contrast, exposure to oral danoprevir 100 mg increased two- to threefold when co-administered with ritonavir. Absolute bioavailability of danoprevir 100 mg was low (1.15 %), but increased more than threefold (3.86 %) when co-administered with ritonavir. Oral ciclosporin 100 mg increased exposure to intravenous danoprevir 2 mg and oral ritonavir 100 mg.

Conclusion

Collectively, these studies provide insight into the transmembrane transport and pharmacokinetics of danoprevir and the mechanisms that underlie a recently reported, three-way drug–drug interaction involving danoprevir, ritonavir, and ciclosporin.

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Acknowledgments

BB, SM, PM, PG, JA, and PS are/were employed by Hoffmann La-Roche Inc., Nutley, NJ, USA, at the time the study was conducted. AP, RP, and CF are/were employed by F. Hoffmann-La Roche Ltd., Basel, Switzerland, at the time the study was conducted. This study was supported by F. Hoffmann-La Roche Ltd. Support for third-party writing assistance for this manuscript, furnished by Blair Jarvis, was provided by F. Hoffmann-La Roche Ltd.

Conflict of interest

All authors were employees of F. Hoffmann-La Roche Ltd. or Hoffmann-La Roche Inc. at the time this research was conducted.

Ethics

The protocol and amendments were reviewed and approved by an independent ethics committee. The study was conducted in accordance with the principles of the Declaration of Helsinki and in compliance with the International Conference on Harmonisation Guideline for Good Clinical Practice (CPMP/ICH/135/95) and the European Union Common Technical Document: Directive 2001/20/EC. All participants provided informed written consent prior to undergoing any study procedures.

Author contributions

All authors critically reviewed and revised the manuscript for intellectual content.

BB—designed research, performed research, acquisition of data, analysis and interpretation of data.

AP—designed research, acquisition of data, analysis and interpretation of data.

SM—performed research, analysis and interpretation of data, revision of manuscript.

PM—designed the research, analysis and interpretation of data, revision of manuscript.

PG—designed research and integrated data.

RP—performed research, acquisition of data, analysis and interpretation of data.

JA—designed research, acquisition of data.

CF—analysis and interpretation of data.

PS—designed research, analysis and interpretation of data.

Author information

Author notes

  1. Sebastian Moreira

    Present address: Pfizer Inc, Madison, NJ, USA

  2. Petra Goelzer

    Present address: Teva Pharmaceuticals, West Chester, PA, USA

  3. Patrick F. Smith

    Present address: d3 Medicine, Parsippany, NJ, USA

Authors and Affiliations

  1. Hoffmann-La Roche Inc., Nutley, NJ, USA

    Barbara J. Brennan, Sebastian Moreira, Peter N. Morcos, Petra Goelzer, Jiney Asthappan & Patrick F. Smith

  2. F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Agnès Poirier, Renée Portmann & Christoph Funk

  3. Roche Innovation Center New York, 430 East 29th Street, New York, NY, 10016, USA

    Barbara J. Brennan

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  1. Barbara J. Brennan
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Corresponding author

Correspondence to Barbara J. Brennan.

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Brennan, B.J., Poirier, A., Moreira, S. et al. Characterization of the Transmembrane Transport and Absolute Bioavailability of the HCV Protease Inhibitor Danoprevir. Clin Pharmacokinet 54, 537–549 (2015). https://doi.org/10.1007/s40262-014-0222-6

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