Pharmacogenomic, pharmacokinetic, and safety analysis of CYP3A4/CYP3A5 polymorphisms of midostaurin in patients with acute myeloid leukemia.

PURPOSE: Midostaurin is predominantly metabolized by cytochrome P450 (CYP) 3A4 to form two active metabolites, CGP62221 and CGP52421. The current analysis from UNIFY, a randomized, double-blind, phase 3 study, investigated the impact of genetic polymorphism of CYP3A4/CYP3A5 on the exposure of midostaurin and its active metabolites, and on treatment-related toxicity in patients with FLT3-mutation-negative acute myeloid leukemia (AML). METHODS: Based on the literature, CYP3A4/CYP3A5 polymorphic variants were selected and further interpreted as individual, combined, and clustered phenotypes. The pharmacokinetic (PK) parameters for midostaurin and the active metabolites were estimated based on concentration data collected after the first dose (full PK profile) and during the induction, consolidation, and post-consolidation phases at trough (pre-dose) and post-dose 3 h. Adverse event (AE) summaries included all treatment-emergent AEs starting on or after study day 1 and starting no later than 30 days after study treatment discontinuation. RESULTS: PK profiles and parameters of midostaurin and its metabolites after the first dose and multiple dosing, at steady state, at the different visits through different phases of the study were generally comparable across CYP3A4/CYP3A5 polymorphic variants and clustered phenotypes. The safety profile of midostaurin in this study was consistent with the known safety profile of midostaurin in FLT3-mutation-positive patients with AML. No meaningful differences were observed in the safety profile of midostaurin versus placebo in patients with CYP3A4/CYP3A5 polymorphic variants and clustered phenotype groups. CONCLUSION: Our extensive pharmacogenomic/PK/safety analysis in patients with AML does not indicate the need for dose adjustments of midostaurin based on CYP3A4/CYP3A5 polymorphic variants. CLINICALTRIALS.GOV NUMBER: NCT03512197.