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Time-dependent inhibition and induction of human cytochrome P450A4/5 by an oral IAP antagonist, LCL161, in vitro and in vivo in healthy subjects

Dhuria, Shyeilla and Einolf, Heidi and Mangold, James and Sen, Suman and Wang, Lai and Gu, Huiping and Cameron, John (2013) Time-dependent inhibition and induction of human cytochrome P450A4/5 by an oral IAP antagonist, LCL161, in vitro and in vivo in healthy subjects. Journal of Clinical Pharmacology, 63 (6). pp. 642-653. ISSN 0091-2700

Abstract

Tumor cells can evade programmed cell death via up-regulation of inhibitor of apoptosis proteins (IAPs). LCL161 is a small molecule oral IAP antagonist in development for use in combination with cytotoxic agents. The effect of LCL161 on CYP3A4/5 (CYP3A) activity was investigated in vitro and in a clinical study. Results in human liver microsomes indicated LCL161 inhibited CYP3A in a concentration- and time-dependent manner (KI of 0.797 uM and kinact of 0.0803 min-1). LCL161 activated human PXR in a reporter gene assay and induced CYP3A4 mRNA up to ~5-fold in human hepatocytes. In healthy subjects, the dual inhibitor and inductive effects of a single dose of LCL161 were characterized using single midazolam doses, given before and at three time points after the LCL161 dose. Midazolam Cmax increased 3.22-fold and AUC(0-inf) increased 9.32-fold when administered four hours after LCL161. Three days later, midazolam Cmax decreased by 27% and AUC(0-inf) decreased by 30%. No drug interaction remained one week later. The strong CYP3A inhibition by LCL161 was accurately predicted using dynamic physiologically-based pharmacokinetic (PBPK) modeling approaches in Simcyp. However, the observed induction effect after the LCL161 dose could not be modeled; suggesting direct enzyme induction by LCL161 was not the underlying mechanism.

Item Type: Article
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Keywords: pharmacokinetics; drug-drug interaction modeling; midazolam; CYP3A time-dependent inhibition; CYP3A induction
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/8476

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