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

Dongwoo Kang, Elizabeth Ludwig, David Jaworowicz, Hannah Huang, Jill Fiedler-Kelly, Jorge Cortes, Siddhartha Ganguly, Samer Khaled, Alwin Krämer, Mark Levis, Giovanni Martinelli, Alexander Perl, Nigel Russell, Malaz Abutarif, Youngsook Choi, Ophelia Yin, Dongwoo Kang, Elizabeth Ludwig, David Jaworowicz, Hannah Huang, Jill Fiedler-Kelly, Jorge Cortes, Siddhartha Ganguly, Samer Khaled, Alwin Krämer, Mark Levis, Giovanni Martinelli, Alexander Perl, Nigel Russell, Malaz Abutarif, Youngsook Choi, Ophelia Yin

Abstract

Purpose: This analysis evaluated the relationship between concentrations of quizartinib and its active metabolite AC886 and QT interval corrected using Fridericia's formula (QTcF) in patients with relapsed/refractory acute myeloid leukemia (AML) treated in the phase 3 QuANTUM-R study (NCT02039726).

Methods: The analysis dataset included 226 patients with AML. Quizartinib dihydrochloride was administered as daily doses of 20, 30, and 60 mg. Nonlinear mixed-effects modeling was performed using observed quizartinib and AC886 concentrations and time-matched mean electrocardiogram measurements.

Results: Observed QTcF increased with quizartinib and AC886 concentrations; the relationship was best described by a nonlinear maximum effect (Emax) model. The predicted mean increase in QTcF at the maximum concentration of quizartinib and AC886 associated with 60 mg/day was 21.1 ms (90% CI, 18.3-23.6 ms). Age, body weight, sex, race, baseline QTcF, QT-prolonging drug use, hypomagnesemia, and hypocalcemia were not significant predictors of QTcF. Hypokalemia (serum potassium < 3.5 mmol/L) was a statistically significant covariate affecting baseline QTcF, but no differences in ∆QTcF (change in QTcF from baseline) were predicted between patients with versus without hypokalemia at the same quizartinib concentration. The use of concomitant QT-prolonging drugs did not increase QTcF further.

Conclusion: QTcF increase was dependent on quizartinib and AC886 concentrations, but patient factors, including sex and age, did not affect the concentration-QTcF relationship. Because concomitant strong cytochrome P450 3A (CYP3A) inhibitor use significantly increases quizartinib concentration, these results support the clinical recommendation of quizartinib dose reduction in patients concurrently receiving a strong CYP3A inhibitor.

Clinical trial registration: NCT02039726 (registered January 20, 2014).

Keywords: AC886; Acute myeloid leukemia; Concentration–QTc analysis; Quizartinib; Relapsed/refractory.

Conflict of interest statement

D. Kang and M. Abutarif are employees and shareholders of Daiichi Sankyo, Inc. E. Ludwig, D. Jaworowicz, H. Huang, and J. Fiedler-Kelly are employees of Cognigen Corporation, which provided consulting services and received financial support from Daiichi Sankyo, Inc, to perform the analyses described. J. Cortes received grants and personal fees from Daiichi Sankyo, Inc, Astellas, Novartis, Pfizer, Jazz Pharmaceuticals, and Bio-Path Holdings and grants from Amphivena and Merus. S. Ganguly received research support from Daiichi Sankyo, Inc, and personal fees from Seattle Genetics. S. Khaled received travel support from Daiichi Sankyo, Inc. A. Krämer received travel support from the University of Heidelberg. M. Levis received grants and personal fees from Astellas and FujiFilm and grants from Agios and Amgen. G. Martinelli received personal fees from Amgen, Daiichi Sankyo, Inc, Celgene, AbbVie, Novartis, and Jazz Pharmaceuticals. A. Perl received grants, personal fees, and travel support from Daiichi Sankyo, Inc, and Astellas, grants and personal fees from Novartis, grants from FujiFilm, and nonfinancial support from Arog. N. Russell has nothing to disclose. Y. Choi and O. Yin are employees of Daiichi Sankyo, Inc.

Figures

Fig. 1
Fig. 1
Observed QTcF data. The mean and 90% confidence interval are shown per visit: C cycle, D day
Fig. 2
Fig. 2
Prediction-corrected visual predictive checks for the final QTcF model. CI confidence interval, QTcF QT interval corrected using Fridericia’s formula
Fig. 3
Fig. 3
Top: ∆QTcF versus concentration for a quizartinib and b AC886. The solid line represents the model-predicted median drug effect predictions; the shaded area represents the 90% uncertainty around median drug effect predictions. Predicted ∆QTcF represents contributions of quizartinib and AC886. Bottom: Contribution of quizartinib and AC886 to ∆QTcF. The solid line represents the median model-predicted ∆QTcF with (c) quizartinib only and (d) AC886 only; the shaded area represents the 90% uncertainty around median drug effect predictions. QTcF QT interval corrected using Fridericia’s formula

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