Dhuria, Shyeilla, Einolf, Heidi, Mangold, James, Sen, Suman, Wang, Lai, 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
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed/23585...
Keywords:	pharmacokinetics; drug-drug interaction modeling; midazolam; CYP3A time-dependent inhibition; CYP3A induction
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed/23585...
Date Deposited:	13 Oct 2015 13:14
Last Modified:	13 Oct 2015 13:14
URI:	https://oak.novartis.com/id/eprint/8476