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- Title
Characterization of the Transmembrane Transport and Absolute Bioavailability of the HCV Protease Inhibitor Danoprevir.
- Authors
Brennan, Barbara; Poirier, Agnès; Moreira, Sebastian; Morcos, Peter; Goelzer, Petra; Portmann, Renée; Asthappan, Jiney; Funk, Christoph; Smith, Patrick
- 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.
- Subjects
PHARMACOKINETICS; DRUG bioavailability; HEPATITIS C virus; PROTEASE inhibitors; DRUG interactions; MEMBRANE proteins
- Publication
Clinical Pharmacokinetics, 2015, Vol 54, Issue 5, p537
- ISSN
0312-5963
- Publication type
Article
- DOI
10.1007/s40262-014-0222-6