PF288 POPULATION PHARMACOKINETIC (POPPK) AND CONCENTRATION‐QTC ANALYSIS OF QUIZARTINIB IN PATIENTS (PTS) WITH FLT3‐ITD–POSITIVE RELAPSED/REFRACTORY (R/R) ACUTE MYELOID LEUKEMIA (AML)

Abstract

Background:Quizartinib is a highly potent and selective FLT3 inhibitor with robust clinical activity in pts with R/R FLT3‐ITD AML.Aims:This analysis was conducted to evaluate the PopPK with quizartinib in a pooled analysis of 7 trials and to evaluate the relationship of quizartinib concentration to QTc in patients from the phase 3 QuANTUM‐R (AC220–007) study.Methods:The PopPK analysis included data from 585 participants enrolled in 5 phase 1 studies, 1 phase 2 study (2689‐CL‐2004), and 1 phase 3 study (QuANTUM‐R). Quizartinib was given as single or multiple doses of 20, 30, 60, and 90 mg (17.7, 26.5, 53, 79.5 mg free base). In QuANTUM‐R, the starting dose was 30 mg/day, increased to 60 mg/day after 2 weeks if QTcF was <450 ms. Patients receiving a concurrent strong CYP3A inhibitor initiated quizartinib at 20 mg/day, with an increase to 30 mg/day if QTcF was <450 ms. Concentration‐QTc analysis included only QuANTUM‐R pts (n = 226). Nonlinear mixed‐effects modeling was performed using observed quizartinib concentrations and time‐matched triplicate ECG measurements.Results:Only strong CYP3A inhibitor use produced a meaningful effect on quizartinib overall exposure (AUC)—an approximately 62% increase. Participant status (AML pts vs healthy participants), albumin level, and body surface area were statistically significant factors, but their effects on quizartinib AUC were <20%. QTcF increased in a concentration‐dependent manner, and the predicted mean increase at the maximum concentration of 60 mg was 21.1 ms (90% CI, 18.3–23.6 ms). Hypokalemia (serum potassium <3.5 mmol/L) was a statistically significant covariate affecting baseline QTcF, but no differences in QTcF increase would be expected at the same quizartinib concentration between patients with and those without hypokalemia.Summary/Conclusion:Strong CYP3A inhibitor use was the only clinically meaningful factor affecting quizartinib PK exposure. QTcF showed an exposure‐dependent increase with respect to quizartinib concentration; but no significant factors, including sex and age, were identified affecting the concentration‐QTc relationship. Results support clinical recommendation of dose reduction in pts receiving strong CYP3A inhibitors because quizartinib exposure is increased significantly in the presence of such agents.