Abstract

Objectives:

The PopPK and C-QTc analyses were conducted to compare the pharmacokinetic (PK) profiles and QTc effect of quizartinib in Japanese and non-Japanese patients.

Methods:

Data for PopPK analysis were obtained from the participants in quizartinib treatment arms of the 7 global studies and 2 Japanese studies. The previously developed PopPK models for quizartinib and its metabolite AC886 were updated using the pooled data. The affect of Japanese population was then evaluated as a covariate on relevant clearance and volume parameters. A sensitivity analysis was performed with only Japanese studies. Mean of triplicate ECG measurement and observed time-matched concentrations of quizartinib and AC886, obtained from 1 Japanese study and 1 global study, were used for concentration-QT interval corrected using Fridericia’s formula (C QTcF) analysis. To establish the relationship between quizartinib and AC886 concentrations and QTcF, a previously developed C-QTcF model was used (Dongwoo Kang et. al., 2019). A full model was formed by inclusion of the affect of Japanese population on baseline QTcF and Emax for quizartinib and AC886.

Results:

The PK of quizartinib in healthy volunteers and non-Japanese and Japanese patients with AML was well characterized by a 3-compartment model with sequential zero- and first-order absorption and linear elimination. The time course of quizartinib and AC886 concentrations in Japanese patients was adequately described using the same structural popPK model with updated parameter estimates. Japanese population was not found to be a statistically significant covariate on quizartinib and AC886 PK parameters. The estimate of quizartinib CL in the sensitivity analysis model was consistent with the CL estimate in the final PopPK model, suggesting that the model was robust enough to accurately characterize quizartinib disposition in the Japanese population alone. The C-QTcF relationship in Japanese patients was adequately described by the same structural model developed for the global study with parameters updated. Covariate of Japanese population was evaluated on baseline QTcF, Emax of quizartinib, and Emax of AC886 and were not statistically significant. The predicted median ΔQTcF at the geometric mean peak plasma quizartinib concentration (378 ng/mL) and corresponding AC886 concentration (205 ng/mL) on Cycle 1 Day 28 after once-daily dosing of quizartinib at 60 mg using actual dosing history in patients was 19.9 msec [90% CI: 17.8, 22.0 msec].

Conclusions:

The PopPK analysis demonstrated similar PK profiles of quizartinib and AC886 in Japanese and non-Japanese AML patients. There were no significant differences in the C-QTcF relationships for quizartinib and AC886 between the Japanese and non-Japanese AML patients. These results support the same dosing regimen for quizartinib in Japanese and non-Japanese AML patients.

Presented at ACoP 11 Virtual Conference, Nov. 9-13, 2020

By Shintaro Nakayama, Masaya Tachibana, Elizabeth Ludwig, David Jaworowicz, Hannah Huang, Jill Fiedler-Kelly, Dongwoo Kang, Malaz Abutarif, Ophelia Yin, Hitoshi Ishizuka, Kazutaka Yoshihara