Xia, B, Barve, A, Heimbach, T, Zhang, T, Gu, H, Wang, L, Einolf, H, Alexander, N, Hanna, I, Ke, J, Mangold, JB, He, H and Sunkara, G (2014) Physiologically based pharmacokinetic modeling for assessing the clinical drug-drug interaction of alisporivir. Eur J Pharm Sci . pp. 103-112.

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

Item Type:	Article
Additional Information:	NIBR author: Xia, B institute: NIBR contributor address: Novartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USANovartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USANovartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA. Electronic address: Tycho.Heimbach@novartis.comNovartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USANovartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USANovartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USANovartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USANovartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USANovartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USANovartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USANovartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USANovartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USANovartis Institutes for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07470, USA
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/24240