Characterization of the transmembrane transport and absolute bioavailability of the HCV protease inhibitor danoprevir.

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.

• Authors: Barbara J Brennan, Agnès Poirier, Sebastian Moreira, Peter N Morcos, Petra Goelzer, Renée Portmann, Jiney Asthappan, Christoph Funk, Patrick F Smith
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 54 Issue 5 Pg. 537-49 (May 2015) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 25488594 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Cyclopropanes
• Isoindoles
• Lactams
• Lactams, Macrocyclic
• Membrane Transport Proteins
• Protease Inhibitors
• Sulfonamides
• Cyclosporine
• danoprevir
• Proline
• Ritonavir

Topics

• Adolescent
• Adult
• Animals
• Antiviral Agents (pharmacokinetics, pharmacology)
• Biological Availability
• CHO Cells
• Carcinoma, Lewis Lung (metabolism)
• Cricetinae
• Cricetulus
• Cross-Over Studies
• Cyclopropanes
• Cyclosporine (pharmacology)
• Dogs
• Drug Interactions
• Female
• Hepatocytes (metabolism)
• Humans
• Isoindoles
• Lactams (pharmacokinetics, pharmacology)
• Lactams, Macrocyclic
• Madin Darby Canine Kidney Cells
• Male
• Membrane Transport Proteins (metabolism)
• Middle Aged
• Proline (analogs & derivatives)
• Protease Inhibitors (pharmacokinetics, pharmacology)
• Randomized Controlled Trials as Topic
• Ritonavir (pharmacology)
• Sulfonamides (pharmacokinetics, pharmacology)
• Swine
• Young Adult