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

Research output: Contribution to journalArticlepeer-review

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).

Original languageEnglish (US)
JournalCancer Chemotherapy and Pharmacology
DOIs
StateAccepted/In press - 2021

Keywords

  • AC886
  • Acute myeloid leukemia
  • Concentration–QTc analysis
  • Quizartinib
  • Relapsed/refractory

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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