Gu, Helen, Dutreix, Catherine, Rebello, Sam, Ouatas, Taoufik, Wang, Lai, Chun, Dung Yu, Einolf, Heidi and He, Handan (2017) Simultaneous physiologically-based pharmacokinetic (PBPK) modeling of parent and active metabolites to investigate complex CYP3A4 drug-drug interaction potential: a case example of midostaurin. Drug metabolism and disposition.

Abstract

Midostaurin (PKC412) is being investigated for the treatment of acute myeloid leukemia (AML) and advanced systemic mastocytosis (ASM). It is extensively metabolized by cytochrome P450 (CYP) 3A4 to form 2 major active metabolites, CGP52421 and CGP62221. In vitro and clinical drug-drug interaction (DDI) studies indicated that midostaurin and its metabolites are substrates, reversible and time-dependent inhibitors, and inducers of CYP3A4. A simultaneous pharmacokinetic model of parent and active metabolites was initially developed by incorporating data from in vitro, preclinical, and clinical pharmacokinetic studies in healthy volunteers and in patients with AML or ASM. The model reasonably predicted changes in midostaurin exposure after single-dose administration with ketoconazole (5.8-fold predicted increase vs 6.1-fold observed) and rifampicin (90% predicted reduction vs 94% observed), as well as changes in midazolam exposure (1.0 predicted ratio vs 1.2 observed) with midostaurin after daily dosing for four days. The qualified model was then applied to predict the DDI effect with other CYP3A4 inhibitors/inducers as well as DDI potential with midazolam under steady-state conditions. The simulated midazolam AUC ratio of 0.54 and the accompanying 1.9-fold increase in the CYP3A4 activity biomarker, 4β-hydroxycholesterol, indicated a weak-to-moderate CYP3A4 induction by midostaurin and its metabolites at steady-state in ASM patients. In conclusion, a simultaneous parent and metabolite modeling approach allowed predictions under steady-state conditions that were not possible to achieve in healthy subjects. Furthermore, endogenous biomarker data enabled evaluation of the net effect of midostaurin and its metabolites on CYP3A4 activity at steady-state and increased confidence in DDI predictions.

Item Type:	Article
Keywords:	PBPK modeling for midostaurin-CYP3A4 interaction
Date Deposited:	19 Dec 2017 00:45
Last Modified:	19 Dec 2017 00:45
URI:	https://oak.novartis.com/id/eprint/33784