Clinical impact of potential drug-drug interactions between midostaurin and posaconazole in FLT3-mutated AML

To determine midostaurin and posaconazole plasma concentrations and investigate adverse events (AEs) resembling drug-drug interactions (DDI) when both drugs were administered concomitantly during induction chemotherapy for acute myeloid leukemia (AML). Patients with FLT3-mutated AML who received midostaurin and posaconazole concomitantly between May 2019 and December 2022 were included and followed up to March 2023. Twice-weekly trough levels for midostaurin and posaconazole were measured with validated liquid chromatography-tandem mass spectrometry methods. Potential DDIs were independently reviewed by two physicians and attributed using the Drug Interaction Probability Scale (DIPS). Population pharmacokinetics analysis was done via nonlinear mixed-effect modeling. In 29 patients, concentrations ranged from 0.6 to 24.5 mg/L for midostaurin and from <30 to 2,572 µg/L for posaconazole. A total of 375 AEs in 66 midostaurin cycles, with 280 AEs classified as grade ≥3, were recorded. Probable DDI with a DIPS score of ≥5 was attributed in 14/375 AEs; no highly probable AEs were registered. Eight AEs led to dose modification or discontinuation of midostaurin in seven patients. Clearance for midostaurin during co-administration with posaconazole was 0.52 L/h (95% CI, 0.42-0.62 L/h). A breakthrough fungal infection was recorded in eight patients (27.5%). DDI of midostaurin and posaconazole is clinically meaningful but infrequent. High inter- and intra-individual variabilities of midostaurin and posaconazole plasma exposure were observed. Midostaurin clearance was delayed during co-administration. Midostaurin therapeutic drug monitoring may serve for decision-making when DDI with CYP3A4 inhibitors is suspected.