The Effect of Efavirenz and Rufinamide on the Pharmacokinetics and Safety of Quizartinib: Two Phase 1 Studies in Healthy Participants

Quizartinib is an oral, potent, selective FMS‐like tyrosine kinase 3 (FLT3) inhibitor, approved for the treatment of FLT3 ‐internal tandem duplication (ITD)–positive acute myeloid leukemia (AML) and under investigation in patients with newly diagnosed FLT3 ‐ITD–negative AML. Quizartinib is metabolized by cytochrome P450 3A (CYP3A) in vitro, primarily into the active metabolite AC886, a CYP3A substrate. These phase 1, open‐label, randomized, parallel‐group trials assessed the effect of efavirenz, a moderate CYP3A inducer, and rufinamide, a weak CYP3A inducer, on the pharmacokinetics of quizartinib and AC886, and the safety and tolerability of quizartinib in healthy participants. Each study enrolled 32 participants; 16 received 60 mg quizartinib alone and 16 received 60 mg quizartinib plus either 600 mg efavirenz or 400 mg rufinamide. Coadministration with efavirenz decreased the maximum plasma concentration ( C max ) and area under the plasma concentration–time curve extrapolated to infinity (AUC inf ) of quizartinib by ~45% and ~90%, respectively, versus quizartinib alone; AC886 C max and AUC inf also decreased by ~68% and ~96%, respectively. Coadministration with rufinamide had modest impact on quizartinib exposure ( C max and AUC inf decreased by ~19% and ~34%, respectively, vs. quizartinib alone). Coadministration of rufinamide and quizartinib decreased AC886 C max and AUC inf by ~47% and ~53%, respectively, versus quizartinib alone. Quizartinib was well tolerated and no new safety signals were observed. These results suggest that concomitant use of quizartinib and moderate CYP3A inducers should be avoided. Concomitant use of weak CYP3A inducers does not warrant dose adjustment, since the impact on quizartinib exposure is clinically nonrelevant.