Population Pharmacokinetics (PopPK) of Quizartinib and Its Active Metabolite AC886 in Patients With Newly Diagnosed (ND) Acute Myeloid Leukemia (AML)
Objectives: Quizartinib, a highly potent, selective FMS-like tyrosine kinase 3 (FLT3) inhibitor, and its active metabolite AC886 exhibit multicompartment PK in patients with relapsed/refractory (R/R) AML [1]. This PopPK analysis aimed to describe the PK characteristics of quizartinib and AC886, to identify and quantify covariate-parameter relationships, and to compare individual steady-state exposures among different subgroups of patients with ND AML from the phase 3 QuANTUM-First study (AC220-A-U302).
Methods: The PopPK analysis included data from 13 studies (nine phase 1, two phase 2, two phase 3). The modeling was first performed on quizartinib data in NONMEM (v7.4.4) software with AC886 data included as an extension to the final quizartinib model. Covariate model building was performed using the stepwise covariate model building procedure. The PopPK analysis included 14,160 quizartinib and 13,399 AC886 observations after oral administration of quizartinib in 932 subjects (273 healthy; 659 with AML) with median body weight of 72 kg and median age of 50 years.
Results: Quizartinib PK was described by a 3-compartment model with a sequential zero- and first-order absorption and a first-order elimination from the central compartment. In the covariate analysis for quizartinib, apparent clearance (CL) of quizartinib was 30% and 26% lower in subjects receiving strong CYP3A inhibitors and Black/African American (AA) subjects, respectively. Apparent volume of distribution for central compartment (Vc) of quizartinib was 17% lower in women, apparent volume of distribution for peripheral compartment 1 of quizartinib was 20% higher in a 60- vs 47-year-old subject, and first-order absorption rate constant was 19% lower in subjects without AML. Relative bioavailability was 1.73 in subjects without AML vs patients with R/R AML and was higher by 27% and 12% with strong and moderate CYP3A inhibitors, respectively. Quizartinib PK in patients with ND AML varied across treatment phases.
The PK of AC886 was described by a 2-compartment model with first-order elimination from the central compartment and first-order formation. The apparent CL of AC886 was 84%, 49%, and 30% higher in subjects without AML, Black/AA subjects, and subjects receiving strong CYP3A inhibitors, respectively. The Vc of AC886 was 3.79-fold higher in subjects receiving strong CYP3A inhibitors. The distributions of individual AUCtau,ss and Cmax,ss of quizartinib and AC886 across different Asian region/country subgroups generally overlapped.
Conclusions: Quizartinib and AC886 PK in patients with ND AML are well characterized by their respective PopPK models. The effect of concomitant CYP3A inhibitors estimated here was consistent with a prior DDI study. Quizartinib PK in patients with ND AML varied across treatment phases. No significant differences in individual steady-state exposures were found among different Asian region/country subgroups. This evaluation supports the use of derived individual exposure metrics in exposure-response analyses.
Reference:
1. Kang D, et al. J Clin Pharmacol. 2020;60:1629-1641.
Author(s)
- Pavan Vaddady, Daiichi Sankyo, Inc. (Presenting Author)
- Giovanni Smania, Pharmetheus AB (CoAuthor)
- Anaïs Glatard, 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)