Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia

Abstract

Quizartinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3-internal tandem duplicationmutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM-R study. Quizartinib was given as a single dose or multiple once-daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed-effects modeling was performed using observed concentrations of quizartinib and AC886. Strong CYP3A inhibitor use resulted in an 82% increase in the area under the curve (AUC) and a 72% increase in the maximum concentration (C max) of quizartinib. Albumin level, age, and body surface area were statistically significant covariates on quizartinib PK. However, their individual effects on quizartinib AUC and C max were <20%. For AC886, strong CYP3A inhibitor use, body surface area and black/African American race were significant covariates. Except for strong CYP3A inhibitor use, the effects on the overall exposure (AUC of quizartinib + AC886) were <20%. The population PK model provided an adequate description of the observed concentrations of quizartinib and AC886 in both healthy volunteers and patients with AML. Only concomitant use of strong CYP3A inhibitors had a clinically meaningful effect on quizartinib PK exposure.

Concentration–QTc analysis of quizartinib in patients with relapsed/refractory acute myeloid leukemia

“…In the drug–drug interaction study, the quizartinib steady-state AUC and C max were predicted to increase by 96% and 86%, respectively, with concomitant administration of the strong CYP3A inhibitor ketoconazole [ 9 ]. In the population PK analysis, quizartinib AUC increased by 82% and C max increased by 72% with concomitant use of a strong CYP3A inhibitor [ 13 ]. Because the current analysis demonstrated a positive exposure–response relationship in C–QTc, these results suggest that dose reduction is necessary for patients who are receiving a concomitant strong CYP3A inhibitor to minimize the risk of QT prolongation.…”

“…The final C–QTc model was utilized to obtain the model-predicted mean ΔQTcF and 90% confidence interval (CI) at the maximum concentration at steady state ( C max,ss ). Individual C max,ss values for patients enrolled in QuANTUM-R who received quizartinib 60 mg were generated using the population PK model [ 13 ], then the geometric mean of quizartinib C max,ss was obtained. When making predictions of ΔQTcF, the bootstrap method was used to account for multiple parameters in the model and the correlation between the parameters [ 14 ].…”

Safety and Pharmacokinetics of Quizartinib Combination Therapy With Standard Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia: Results from Two Phase 1 Trials in Japan and China

“…17 The effect of strong CYP3A inhibitors on quizartinib exposure has also been reported in a population PK analysis. 18 An open-label, randomized, parallel-group study in healthy volunteers showed minimal effects of lansoprazole on the plasma concentrations of quizartinib and AC886. 19 A Phase 1 dose-escalation study was conducted in 19 patients with newly diagnosed AML (9 patients were FLT3-ITD positive) in the United States (NCT01390337).…”

“…14 The pharmacokinetic (PK) and drug-drug interaction profiles of quizartinib have been investigated in several studies. [15][16][17][18][19] Coadministration of cytochrome P450 (CYP) 3A inhibitors (ketoconazole or fluconazole) with quizartinib increased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) of quizartinib, especially with ketoconazole. The half-life was ex-tended, but the time to reach maximum plasma concentration (t max ) remained unchanged, except for AC886 when quizartinib was coadministered with ketoconazole.…”

“…The pharmacokinetic (PK) and drug‐drug interaction profiles of quizartinib have been investigated in several studies 15‐19 . Coadministration of cytochrome P450 (CYP) 3A inhibitors (ketoconazole or fluconazole) with quizartinib increased the area under the plasma concentration‐time curve (AUC) and maximum plasma concentration (C max ) of quizartinib, especially with ketoconazole.…”