title: Physiologically based pharmacokinetic modeling for assessing the clinical drug-drug interaction of alisporivir.
abstract: Alisporivir is a novel cyclophilin-binding molecule with potent anti-hepatitis C virus (HCV) activity. In vitro data from human liver microsomes suggest that alisporivir is a substrate and a time-dependent inhibitor (TDI) of CYP3A4. The aim of the current work was to develop a novel physiologically based pharmacokinetic (PBPK) model to quantitatively assess the magnitude of CYP3A4 mediated drug-drug interactions with alisporivir as the substrate or victim drug. Towards that, a Simcyp PBPK model was developed by integrating in vitro data with in vivo clinical findings to characterize the clinical pharmacokinetics of alisporivir and further assess the magnitude of drug-drug interactions. Incorporated with absorption, distribution, elimination, and TDI data, the model accurately predicted AUC, Cmax, and tmax values after single or multiple doses of alisporivir with a prediction deviation within ± 32%. The model predicted an alisporivir AUC increase by 9.4-fold and a decrease by 86% when alisporivir was co-administrated with ketoconazole (CYP3A4 inhibitor) or rifampin (CYP3A4 inducer), respectively. Predictions were within ± 20% of the observed changes. In conclusion, the PBPK model successfully predicted the alisporivir PK and the magnitude of drug-drug interactions.
authors.affiliation: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA.
authors.forename: Binfeng
authors.initials: B
authors.lastname: Xia
authors.affiliation: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA.
authors.forename: Avantika
authors.initials: A
authors.lastname: Barve
authors.affiliation: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA. Electronic address: Tycho.Heimbach@novartis.com.
authors.forename: Tycho
authors.initials: T
authors.lastname: Heimbach
authors.affiliation: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Gu
authors.affiliation: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA.
authors.forename: Lai
authors.initials: L
authors.lastname: Wang
authors.affiliation: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Einolf
authors.affiliation: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA.
authors.forename: Natalya
authors.initials: N
authors.lastname: Alexander
authors.affiliation: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA.
authors.forename: Imad
authors.initials: I
authors.lastname: Hanna
authors.affiliation: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA.
authors.forename: June
authors.initials: J
authors.lastname: Ke
authors.affiliation: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Mangold
authors.affiliation: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA.
authors.forename: Handan
authors.initials: H
authors.lastname: He
authors.affiliation: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA.
authors.forename: Gangadhar
authors.initials: G
authors.lastname: Sunkara
mesh_terms: D000284:Administration, Oral; D018938:Caco-2 Cells; D016572:Cyclosporine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000737:chemistry / Q000494:pharmacology*; D008954:Models, Biological; D012293:Rifampin / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole; C499715:alisporivir; D012293:Rifampin
keywords: Alisporivir; CL; CYP3A4; Drug–drug interaction; Physiologically-based pharmacokinetic (PBPK) model; Time-dependent inhibition; clearance