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

3 Scopus citations

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 (E max) 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)
Pages (from-to)513-523
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume87
Issue number4
DOIs
StatePublished - Apr 2021

Keywords

  • AC886
  • Acute myeloid leukemia
  • Concentration–QTc analysis
  • Quizartinib
  • Relapsed/refractory
  • Benzothiazoles/pharmacology
  • Humans
  • Leukemia, Myeloid, Acute/drug therapy
  • Middle Aged
  • Phenylurea Compounds/pharmacology
  • Male
  • Electrocardiography/drug effects
  • Dose-Response Relationship, Drug
  • Cytochrome P-450 CYP3A Inhibitors/pharmacology
  • Aged, 80 and over
  • Adult
  • Female
  • Aged

ASJC Scopus subject areas

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

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