title: The effects of CYP3A4 induction and inhibition on the pharmacokinetics of alisporivir in humans.
abstract: In vitro data suggest that alisporivir is a substrate and inhibitor of CYP3A4 and P-gp. Hence, the potential for drug-drug interactions when alisporivir is co-administered with CYP3A4 and/or P-gp inhibitors such as ketoconazole, azithromycin and CYP3A4 inducers such as rifampin were evaluated in three separate clinical studies. Co-administration with ketoconazole (a strong CYP3A4 inhibitor) increased the Cmax , AUC and terminal elimination half-life of alisporivir by approximately two-, eight- ,and threefold, respectively. Co-administration with azithromycin (a putative weak CYP3A4 inhibitor and substrate) had no impact on the Cmax and AUC of alisporivir. Rifampin (a CYP3A4 inducer) caused an approximate 90% reduction in alisporivir Cmax and AUC and a fourfold reduction in alisporivir terminal elimination half-life. Alisporivir as an inhibitor of CYP3A4 caused a 39% increase in azithromycin exposure. The results from these studies establish alisporivir as a sensitive CYP3A4 substrate in vivo. Consequently, co-administered potent CYP3A4 inhibitors and inducers are likely to cause clinically significant changes in the exposure to alisporivir.
authors.affiliation: Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
authors.forename: Avantika
authors.initials: A
authors.lastname: Barve
authors.affiliation: Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kovacs
authors.affiliation: Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
authors.forename: June
authors.initials: J
authors.lastname: Ke
authors.affiliation: Debiopharm International SA, Lausanne, Switzerland.
authors.forename: Rafael
authors.initials: R
authors.lastname: Crabbe
authors.affiliation: Debiopharm International SA, Lausanne, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Grosgurin
authors.affiliation: Debiopharm International SA, Lausanne, Switzerland.
authors.forename: Annick
authors.initials: A
authors.lastname: Menetrey
authors.affiliation: Debiopharm International SA, Lausanne, Switzerland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Nicolas-Métral
authors.affiliation: Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Dabovic
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Dole
authors.affiliation: Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Praestgaard
authors.affiliation: Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
authors.forename: Gangadhar
authors.initials: G
authors.lastname: Sunkara
authors.affiliation: Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stein
mesh_terms: D019540:Area Under Curve; D017963:Azithromycin / Q000008:administration & dosage* / Q000009:adverse effects; D001530:Belgium; D001711:Biotransformation; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage* / Q000009:adverse effects; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D004347:Drug Interactions; D005260:Female; D005431:Florida; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009518:New York; D012293:Rifampin / Q000008:administration & dosage* / Q000009:adverse effects; D013379:Substrate Specificity
chemical_list: D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D007166:Immunosuppressive Agents; D017963:Azithromycin; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; C499715:alisporivir; D012293:Rifampin
keywords: CYP3A4; alisporivir; drug-drug interaction; pharmacokinetics