Drug Interaction Report

Coadministration with mild or moderate inhibitors of CYP450 3A4 is not expected to have clinically significant effects on the pharmacokinetics of quizartinib or its major circulating active metabolite, AC886. According to the prescribing information, quizartinib is primarily metabolized via oxidation by CYP450 3A4/5 in vitro, and AC886 is formed and metabolized by CYP450 3A4/5. Following coadministration of a single 53 mg dose of quizartinib with ketoconazole, a potent CYP450 3A4 inhibitor, quizartinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 17% and 94%, respectively, while the Cmax and AUC of AC886 decreased by 60% and 94%, respectively. By contrast, clinically significant changes in the Cmax and AUC of quizartinib and AC886 were not observed following coadministration of single-dose quizartinib with fluconazole, a moderate CYP450 3A4 inhibitor. Therefore, no dosage adjustments are recommended when quizartinib is coadministered with mild and moderate CYP450 3A4 inhibitors.

Concurrent use of cimetidine and ethanol may result in increased ethanol concentrations. The mechanism appears to be due to inhibition of gastric alcohol dehydrogenase by cimetidine, leading to increased bioavailability of the alcohol and inhibition of hepatic metabolism of alcohol. The clinical significance of this interaction is limited. More importantly, patients requiring cimetidine for gastrointestinal disease should be counseled to avoid alcohol to prevent worsening of their disease. The other H-2 receptor antagonists appear to have minimal effects on the concentrations of alcohol.

Caffeine effects may be increased in patients also taking cimetidine. The mechanism may be due to decreased caffeine metabolism induced by cimetidine. Although adequate clinical data are lacking, a reduction in dose or elimination of caffeine may be needed if excess CNS stimulation is observed.

H2 antagonists may reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.