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Effect of Food on the Pharmacokinetics of Quizartinib.

ABSTRACT: Quizartinib is an oral, highly potent, and selective type II FMS-like tyrosine kinase 3 inhibitor in development for acute myeloid leukemia. This parallel-group study evaluated potential food effects on quizartinib absorption in healthy subjects who received a single 30-mg dose after overnight fasting (n = 34) or a high-fat, high-calorie meal (n = 30). Blood samples were collected through 504 hours after dosing, and pharmacokinetic parameters calculated were maximum observed concentration (Cmax ) and area under plasma concentration-time curve from time 0 to last quantifiable concentration (AUClast ) and from time 0 to infinity (AUCinf ). Mean quizartinib pharmacokinetic profiles were similar under fasted and fed conditions. The geometric least squares means ratios (%) for fed/fasted and associated 90% confidence intervals (CIs) for Cmax , AUClast , and AUCinf were 91.58 (82.15-102.08), 105.39 (90.79-122.35), and 108.39 (91.54-128.34), respectively. The 90%CI for the ratio fell within the 80% to 125% limits for Cmax and AUClast , with 90%CI for AUCinf slightly outside the limits (ie, 128%). Food delayed quizartinib time to Cmax by 2 hours. All adverse events were either mild or moderate; no discontinuations due to adverse events occurred. Based on these results, quizartinib can be administered without regard to food.

SUBMITTER: Li J

PROVIDER: S-EPMC7027461 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Effect of Food on the Pharmacokinetics of Quizartinib.

Li Jianke J Holmes Melissa M Kankam Martin M Trone Denise D Mendell Jeanne J Gammon Guy G

Clinical pharmacology in drug development 20200108 2

Quizartinib is an oral, highly potent, and selective type II FMS-like tyrosine kinase 3 inhibitor in development for acute myeloid leukemia. This parallel-group study evaluated potential food effects on quizartinib absorption in healthy subjects who received a single 30-mg dose after overnight fasting (n = 34) or a high-fat, high-calorie meal (n = 30). Blood samples were collected through 504 hours after dosing, and pharmacokinetic parameters calculated were maximum observed concentration (C<sub ...[more]

PMID: 31916418

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Project description:AimsQuizartinib is an oral, highly potent and selective next-generation FMS-like tyrosine kinase 3 (FLT3) inhibitor under investigation in patients with FLT3-internal tandem duplication-mutated acute myeloid leukaemia. This drug-drug interaction study assessed the pharmacokinetics (PK) of quizartinib when coadministered with strong or moderate cytochrome P450 3A (CYP3A) inhibitors.MethodsIn this parallel-group study, subjects were randomised to receive: (i) quizartinib + ketoconazole; (ii) quizartinib + fluconazole; or (iii) quizartinib alone. On Days 1-28, subjects received ketoconazole 200 mg or fluconazole 200 mg twice daily, and on Day 8, all subjects received a single 30-mg quizartinib dose. Blood samples were collected for PK analyses, steady-state PK parameters were simulated by superpositioning, and safety was assessed.ResultsNinety-three healthy subjects were randomised; 86 completed the study. When administered with ketoconazole, geometric mean ratios (90% confidence interval) for quizartinib maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity were 117% (105%, 130%) and 194% (169%, 223%), respectively, vs quizartinib alone. Steady-state PK simulation demonstrated ~2-fold increase of both steady-state Cmax and AUC from time 0 to the end of the dosing interval when quizartinib was administered with ketoconazole due to accumulation of quizartinib at steady state. When administered with fluconazole, geometric mean ratios (90% confidence interval) for quizartinib Cmax and AUC from time 0 extrapolated to infinity were 111% (100%, 124%) and 120% (104%, 138%), respectively, vs quizartinib alone. Overall, 5.4% of subjects experienced quizartinib-related adverse events; no serious adverse events or deaths occurred.ConclusionsThese results suggest reducing the dose of quizartinib when coadministered with a strong CYP3A inhibitor, but not with a moderate or weak CYP3A inhibitor. This dose reduction was implemented in phase 3 evaluation of quizartinib.

Project description:Dronabinol is a pharmaceutical tetrahydrocannabinol originally developed as an oral capsule. A dronabinol oral solution was recently approved, and the effects of food on absorption and bioavailability of the oral solution versus capsules were compared in an open-label, single-dose, 3-period crossover study. Healthy volunteers were randomized to either dronabinol oral solution 4.25 mg (fed) or dronabinol capsule 5 mg (fed or fasted). Dosing was separated by a 7-day washout period. Plasma pharmacokinetics were evaluated for dronabinol and its major metabolite, 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-?9-THC). Pharmacokinetic data were available for analysis in 54 volunteers. In the fed state, initial dronabinol absorption was faster with oral solution versus capsule (mean time to the first measurable concentration, 0.15 vs 2.02 hours, respectively), with 100% and 15% of volunteers, respectively, having detectable plasma dronabinol levels 30 minutes postdose. There was less interindividual variability in plasma dronabinol concentration during early absorption with oral solution versus capsule. Compared with the fasted state, mean area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-t ) increased by 2.1- and 2.4-fold for dronabinol oral solution and capsule, respectively, when taken with food. Mean time to maximum plasma concentration was similarly delayed for dronabinol oral solution with food (7.7 hours) and capsule with food (5.6 hours) versus capsule with fasting (1.7 hours). Under fed conditions, AUC0-t and area under the plasma concentration-time curve from time zero to infinity were similar for the oral solution versus capsule based on 11-OH-?9-THC levels. An appreciable food effect was observed for dronabinol oral solution and capsules. Dronabinol oral solution may offer therapeutic benefit to patients, given its rapid and lower interindividual absorption variability versus dronabinol capsule.

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Effect of Food on the Pharmacokinetics of Quizartinib.

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Effect of Food on the Pharmacokinetics of Quizartinib.

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