Dongwoo Kang1, Elizabeth Ludwig2, David Jaworowicz2, Hannah Huang2, Jill Fiedler-Kelly2, Jorge Cortes3, Siddhartha Ganguly4, Samer Khaled5, Alwin Krämer6, Mark Levis7, Giovanni Martinelli8, Alexander Perl9, Nigel Russell10, Malaz Abutarif11, Youngsook Choi11, Ophelia Yin11. 1. Daiichi Sankyo, Inc, Basking Ridge, NJ, USA. dkang@dsi.com. 2. Cognigen Corporation, a Simulations Plus Company, Buffalo, NY, USA. 3. Georgia Cancer Center at Augusta University, Augusta, GA, USA. 4. University of Kansas Cancer Center, Fairway, KS, USA. 5. City of Hope, Arcadia, CA, USA. 6. Clinical Cooperation Unit Molecular Hematology/Oncology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. 7. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA. 8. Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. 9. Division of Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. 10. Centre for Clinical Haematology, Nottingham University Hospital, Nottingham, UK. 11. Daiichi Sankyo, Inc, Basking Ridge, NJ, USA.
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).
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).
Authors: Jorge Cortes; Alexander E Perl; Hartmut Döhner; Hagop Kantarjian; Giovanni Martinelli; Tibor Kovacsovics; Philippe Rousselot; Björn Steffen; Hervé Dombret; Elihu Estey; Stephen Strickland; Jessica K Altman; Claudia D Baldus; Alan Burnett; Alwin Krämer; Nigel Russell; Neil P Shah; Catherine C Smith; Eunice S Wang; Norbert Ifrah; Guy Gammon; Denise Trone; Deborah Lazzaretto; Mark Levis Journal: Lancet Oncol Date: 2018-05-31 Impact factor: 41.316
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Authors: Jorge E Cortes; Martin S Tallman; Gary J Schiller; Denise Trone; Guy Gammon; Stuart L Goldberg; Alexander E Perl; Jean-Pierre Marie; Giovanni Martinelli; Hagop M Kantarjian; Mark J Levis Journal: Blood Date: 2018-06-06 Impact factor: 22.113
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