Concentration-QTcF Analysis of Quizartinib in Patients With Newly Diagnosed (ND) Acute Myeloid Leukemia (AML)
Objectives: Quizartinib is an oral, highly potent and selective type II FMS-like tyrosine kinase 3 (FLT3) inhibitor with single-agent activity in relapsed/refractory (R/R) FLT3 internal tandem duplication–positive (FLT3-ITD+) AML [1]. Quizartinib prolongs the Fridericia-corrected QT interval (QTcF) in a concentration-dependent manner, predominantly through inhibition of the slowly activating component of delayed rectifier potassium currents, IKs [2]. The data for this analysis were derived from the phase 3 QuANTUM-First study, which compared the effect of quizartinib vs placebo (in combination with standard induction and consolidation chemotherapy [± allogeneic hematopoietic stem cell transplant], then administered as continuation single-agent therapy for ≤3 years) on overall survival in patients with ND FLT3-ITD+ AML. In continuation therapy, quizartinib was initiated at 30 mg once daily (QD) and increased to 60 mg QD on day 16 if QTcF was ≤450 ms on day 15. The aim of this analysis was to describe the relationship between quizartinib concentrations and QTcF for patients with ND AML and to support the quizartinib dosing regimen tested in QuANTUM-First.
Methods: A population pharmacokinetics-pharmacodynamics model was developed to describe the relationship between quizartinib concentrations and QTcF. Nonlinear mixed-effects modeling approaches were used to analyze QTcF data. The covariate analysis was performed using stepwise covariate model-building with adaptive scope reduction. Absolute values of QT interval corrected for heart rate using QTcF were used for the concentration-QTcF analysis. The modeling was first performed on placebo data, and then data from the quizartinib arm were included in the analysis. The QTcF analysis data set included 531 patients (placebo, 268; quizartinib, 263), and 22,764 observations (placebo, 15,477; quizartinib, 7287 with matched plasma concentrations).
Results: The exposure-response relationship between quizartinib concentration and QTcF was described by a direct response model, where QTcF prolongation was linked to quizartinib concentrations through a maximum effect (Emax) function. The model accounted for the effects of age and hypokalemia on baseline QTcF, as well as diurnal variations in QT interval using an empirical change in baseline based on clock time deciles. Interindividual variability (IIV) terms were included in the baseline QTcF, Emax, and concentration at half-maximum effect parameters. Statistically significant covariates on Emax were age, daunorubicin, hypokalemia, and calcium levels but increased IIV when included and were not retained. The median model-predicted change from baseline in QTcF at maximum concentration at steady-state in patients with ND AML during the continuation phase at 30 mg and 60 mg was 18.4 ms (90% CI, 16.3 ms-20.5 ms) and 24.1 ms (90% CI, 21.4 ms-26.6 ms), respectively.
Conclusions: An Emax model best described the relationship between quizartinib concentration and QTcF. The results of the analysis in patients with ND AML were consistent with those from a previous analysis in patients with R/R AML [2].
References:
1. Cortes JE, et al. Lancet Oncol. 2019;20:984-997.
2. Kang D, et al. Cancer Chemother Pharmacol. 2021;87:513-523.
Author(s)
- Pavan Vaddady, Daiichi Sankyo, Inc. (Presenting Author)
- Giovanni Smania, Pharmetheus AB (CoAuthor)
- Martin Bergstrand, Pharmetheus AB (CoAuthor)
- Shintaro Nakayama, Daiichi Sankyo Co., Ltd. (CoAuthor)
- Hiroyuki Inoue, Daiichi Sankyo Co., Ltd. (CoAuthor)
- Abhinav Kurumaddali, Daiichi Sankyo, Inc. (CoAuthor)
- Malaz Abutarif, Daiichi Sankyo, Inc. (CoAuthor)
- Ming Zheng, Daiichi Sankyo, Inc. (CoAuthor)