Effect of Food on the Pharmacokinetics of Quizartinib

Li, Jianke; Holmes, Melissa F.; Kankam, Martin; Trone, Denise; Mendell, Jeanne; Gammon, Guy

doi:10.1002/cpdd.770

Cited by 5 publications

(5 citation statements)

References 26 publications

(72 reference statements)

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“…Take sorafenib for example, considering possibly decreased bioavailability under high-fat meal, sorafenib can be administered without food or with low/moderate-fat meal (Di Gion et al, 2011). In contrast, sunitinib and quizartinib can be administered without regard to food (Di Gion et al, 2011;Li et al, 2020), and the bioavailability of midostaurin and cabozantinib increases significantly under high-fat fed condition (Wang et al, 2008;Lacy et al, 2017). Additionally, pexidartinib is recommended to be administered with a low-fat meal (Zahir et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

“…Simultaneously, duration of therapy was reported in sorafenib, gilteritinib and quizartinib with the range of 1.94-4.6 months (Awada et al, 2005;Borthakur et al, 2011;Semrad et al, 2012;Chen et al, 2014;Lin et al, 2017;Perl et al, 2017;Cortes J. et al, 2018;Cortes JE. et al, 2018;Usuki et al, 2018;Cortes et al, 2019;Perl et al, 2019;Usuki et al, 2019;Burchert et al, 2020;Li et al, 2020;Fierro-Maya et al, 2021;Hosono et al, 2021;Huh et al, 2021;Numan et al, 2022;Dumas et al, 2023;Kudo et al, 2023).…”

Section: Efficacy Survival Outcomementioning

confidence: 99%

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Efficacy and safety of FLT3 inhibitors in monotherapy of hematological and solid malignancies: a systemic analysis of clinical trials

Zhao,

Zhang,

Ding

et al. 2024

Front. Pharmacol.

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Introduction: FLT3 mutations are closely associated with the occurrence of hematological and solid malignancies, especially with acute myeloid leukemia. Currently, several FLT3 inhibitors are in clinical trials, and some have been applied in clinic. However, the safety, efficacy and pharmacodynamics of these FLT3 inhibitors have not been systemically analyzed before.Methods: We searched and reviewed clinical trial reports on the monotherapy of 13 FLT3 inhibitors, including sorafenib, lestaurtinib, midostaurin, gilteritinib, quizartinib, sunitinib, crenolanib, tandutinib, cabozantinib, pexidartinib, pacritinib, famitinib, and TAK-659 in patients with hematological and solid malignancies before May 31, 2023.Results: Our results showed the most common adverse events (AEs) were gastrointestinal adverse reactions, including diarrhea, hand-foot syndrome and nausea, while the most common hematological AEs were febrile neutropenia, anemia, and thrombocytopenia. Based on the published data, the mean overall survival (OS) and the mean progression-free survival (PFS) were 9.639 and 5.905 months, respectively. The incidence of overall response rate (ORR), complete remission (CR), partial response (PR), and stable disease (SD) for all these FLT3 inhibitors was 29.0%, 8.7%, 16.0%, and 42.3%, respectively. The ORRs of FLT3 inhibitors in hematologic malignancies and solid tumors were 40.8% and 18.8%, respectively, indicating FLT3 inhibitors were more effective for hematologic malignancies than for solid tumors. In addition, time to maximum plasma concentration (Tmax) in these FLT3 inhibitors ranged from 0.7-12.0 hours, but the elimination half-life (T1/2) range was highly variable, from 6.8 to 151.8 h.Discussion: FLT3 inhibitors monotherapy has shown significant anti-tumor effect in clinic, and the effectiveness may be further improved through combination medication.

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Section: Discussionmentioning

confidence: 99%

Section: Efficacy Survival Outcomementioning

confidence: 99%

Efficacy and safety of FLT3 inhibitors in monotherapy of hematological and solid malignancies: a systemic analysis of clinical trials

Zhao,

Zhang,

Ding

et al. 2024

Front. Pharmacol.

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“…This assay was the same as the first, except that it had a lower calibration range of 0.5 to 500 ng/mL and lower limits of quantification of 0.5 ng/mL for both quizartinib and AC886. Crossvalidation was conducted between the 2 assays using 12,24,36,48,72,96,120,144,168,192,216,288,360,432, and 504 hours postdose AC220-019 27 1 64 1374 1259 Single dose of 30 mg…”

Section: Bioanalytical Methodsmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia

Kang

Ludwig

Jaworowicz

et al. 2020

The Journal of Clinical Pharma

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Quizartinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3-internal tandem duplicationmutated 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 (C max) of quizartinib. Albumin level, age, and body surface area were statistically significant covariates on quizartinib PK. However, their individual effects on quizartinib AUC and C max 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.

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“…14 The pharmacokinetic (PK) and drug-drug interaction profiles of quizartinib have been investigated in several studies. [15][16][17][18][19] Coadministration of cytochrome P450 (CYP) 3A inhibitors (ketoconazole or fluconazole) with quizartinib increased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) of quizartinib, especially with ketoconazole. The half-life was ex-tended, but the time to reach maximum plasma concentration (t max ) remained unchanged, except for AC886 when quizartinib was coadministered with ketoconazole.…”

mentioning

confidence: 99%

“…The pharmacokinetic (PK) and drug‐drug interaction profiles of quizartinib have been investigated in several studies 15‐19 . Coadministration of cytochrome P450 (CYP) 3A inhibitors (ketoconazole or fluconazole) with quizartinib increased the area under the plasma concentration‐time curve (AUC) and maximum plasma concentration (C max ) of quizartinib, especially with ketoconazole.…”

mentioning

confidence: 99%

Safety and Pharmacokinetics of Quizartinib Combination Therapy With Standard Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia: Results from Two Phase 1 Trials in Japan and China

Qi,

Choi,

Ota

et al. 2024

Clinical Pharm in Drug Dev

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Quizartinib is a potent, oral, second‐generation, selective type II FMS‐like receptor tyrosine kinase 3 (FLT3) inhibitor. It has shown improved overall survival in a randomized, multinational, Phase 3 (QuANTUM‐First) study in patients with FLT3‐internal tandem duplication (ITD)‐positive newly diagnosed acute myeloid leukemia. We conducted 2 Phase 1b studies in Japan and China to evaluate the safety, pharmacokinetics, and efficacy of quizartinib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Quizartinib was started at a dose level of 20 mg/day and then escalated to 40 mg/day, the dose used in the Phase 3 study. Seven patients were enrolled according to the 3 + 3 dose‐escalation method in each study, including 3 patients who were FLT3‐ITD positive. No dose‐limiting toxicities were observed at dose levels up to 40 mg/day in both studies. Grade 3 or higher, quizartinib‐related, treatment‐emergent adverse events included febrile neutropenia, hematologic toxicities, and infections. QT prolongation on electrocardiogram was observed in 5 patients. The pharmacokinetics of quizartinib and its metabolite AC886 were similar between the studies and consistent with previous findings in the United States. We confirmed the tolerability of Japanese and Chinese patients to the dose of quizartinib and chemotherapy regimens used in the QuANTUM‐First study.

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Effect of Food on the Pharmacokinetics of Quizartinib

Cited by 5 publications

References 26 publications

Efficacy and safety of FLT3 inhibitors in monotherapy of hematological and solid malignancies: a systemic analysis of clinical trials

Efficacy and safety of FLT3 inhibitors in monotherapy of hematological and solid malignancies: a systemic analysis of clinical trials

Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia

Safety and Pharmacokinetics of Quizartinib Combination Therapy With Standard Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia: Results from Two Phase 1 Trials in Japan and China

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