TY - JOUR T1 - Simultaneous physiologically-based pharmacokinetic (PBPK) modeling of parent and active metabolites to investigate complex CYP3A4 drug-drug interaction potential: a case example of midostaurin JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.117.078006 SP - dmd.117.078006 AU - Helen Gu AU - Catherine Dutreix AU - Sam Rebello AU - Taoufik Ouatas AU - Lai Wang AU - Dung Yu Chun AU - Heidi J Einolf AU - Handan He Y1 - 2017/01/01 UR - http://dmd.aspetjournals.org/content/early/2017/11/08/dmd.117.078006.abstract N2 - Midostaurin (PKC412) is being investigated for the treatment of acute myeloid leukemia (AML) and advanced systemic mastocytosis (advSM). 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 advSM. The model reasonably predicted changes in midostaurin exposure after single-dose administration with ketoconazole (5.8-fold predicted vs 6.1-fold observed increase) and rifampicin (90% predicted vs 94% observed reduction) as well as changes in midazolam exposure (1.0 predicted vs 1.2 observed ratio) after daily dosing of midostaurin for 4 days. The qualified model was then applied to predict the DDI effect with other CYP3A4 inhibitors or inducers and DDI potential with midazolam under steady-state conditions. The simulated midazolam AUC ratio of 0.54 and accompanying observed 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 patients with advSM. In conclusion, a simultaneous parent-and-active-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. ER -