Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and 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, Jeanne Mendell, Ophelia Yin

Research output: Contribution to journalArticlepeer-review

Abstract

Quizartinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3-internal tandem duplication–mutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM-R study. Quizartinib was given as a single dose or multiple once-daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed-effects modeling was performed using observed concentrations of quizartinib and AC886. Strong CYP3A inhibitor use resulted in an 82% increase in the area under the curve (AUC) and a 72% increase in the maximum concentration (Cmax) of quizartinib. Albumin level, age, and body surface area were statistically significant covariates on quizartinib PK. However, their individual effects on quizartinib AUC and Cmax were <20%. For AC886, strong CYP3A inhibitor use, body surface area and black/African American race were significant covariates. Except for strong CYP3A inhibitor use, the effects on the overall exposure (AUC of quizartinib + AC886) were <20%. The population PK model provided an adequate description of the observed concentrations of quizartinib and AC886 in both healthy volunteers and patients with AML. Only concomitant use of strong CYP3A inhibitors had a clinically meaningful effect on quizartinib PK exposure.

Original languageEnglish (US)
Pages (from-to)1629-1641
Number of pages13
JournalJournal of Clinical Pharmacology
Volume60
Issue number12
DOIs
StatePublished - Dec 1 2020

Keywords

  • AC886
  • acute myeloid leukemia
  • population pharmacokinetics
  • quizartinib
  • relapsed/refractory

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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