TY - JOUR
T1 - Concentration–QTc analysis of quizartinib in 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 - Yin, Ophelia
N1 - Funding Information:
Medical editorial assistance was provided by Melanie Vishnu, PhD (SciMentum, Inc, a Nucleus Global company), funded by Daiichi Sankyo, Inc, in accordance with Good Publication Practice guidelines.
Funding Information:
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.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/4
Y1 - 2021/4
N2 - 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).
AB - 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).
KW - AC886
KW - Acute myeloid leukemia
KW - Concentration–QTc analysis
KW - Quizartinib
KW - Relapsed/refractory
KW - Benzothiazoles/pharmacology
KW - Humans
KW - Leukemia, Myeloid, Acute/drug therapy
KW - Middle Aged
KW - Phenylurea Compounds/pharmacology
KW - Male
KW - Electrocardiography/drug effects
KW - Dose-Response Relationship, Drug
KW - Cytochrome P-450 CYP3A Inhibitors/pharmacology
KW - Aged, 80 and over
KW - Adult
KW - Female
KW - Aged
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U2 - 10.1007/s00280-020-04204-y
DO - 10.1007/s00280-020-04204-y
M3 - Article
C2 - 33415416
AN - SCOPUS:85099111739
SN - 0344-5704
VL - 87
SP - 513
EP - 523
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 4
ER -