TY - JOUR
T1 - Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia
AU - Kang, Dongwoo
AU - Ludwig, Elizabeth
AU - Jaworowicz, David
AU - Huang, Hannah
AU - Fiedler-Kelly, Jill
AU - Cortes, Jorge
AU - Ganguly, Siddhartha
AU - Khaled, Samer
AU - Krämer, Alwin
AU - Levis, Mark
AU - Martinelli, Giovanni
AU - Perl, Alexander
AU - Russell, Nigel
AU - Abutarif, Malaz
AU - Choi, Youngsook
AU - Mendell, Jeanne
AU - Yin, Ophelia
N1 - Funding Information:
D. Kang is an employee and shareholder 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 Biopath Holdings and grants from Amphivena. Mercus. 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, and grants from FujiFilm, and nonfinancial support from Arog. N. Russell has nothing to disclose. M. Abutarif is an employee and shareholder of Daiichi Sankyo, Inc. Y. Choi and O. Yin are employees of Daiichi Sankyo, Inc. J. Mendell was employed by Daiichi Sankyo, Inc., at the time the work was conducted. Medical editorial assistance was provided by Scott Battle, PhD (Medical Expressions, a Nucleus Global company), funded by Daiichi Sankyo in accordance with Good Publication Practice guidelines.
Funding Information:
This study was funded by Daiichi Sankyo, Inc.
Publisher Copyright:
© 2020 Daiichi Sankyo, Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
KW - AC886
KW - acute myeloid leukemia
KW - population pharmacokinetics
KW - quizartinib
KW - relapsed/refractory
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U2 - 10.1002/jcph.1680
DO - 10.1002/jcph.1680
M3 - Article
C2 - 32598495
AN - SCOPUS:85087168263
VL - 60
SP - 1629
EP - 1641
JO - Journal of Clinical Pharmacology
JF - Journal of Clinical Pharmacology
SN - 0091-2700
IS - 12
ER -