Drug Interaction Report

GENERALLY AVOID: Coadministration of pexidartinib with strong CYP450 3A4 inducers may decrease the plasma concentrations and therapeutic effects of pexidartinib. The proposed mechanism is induction of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of pexidartinib. Concomitant administration of rifampin, a strong CYP450 3A4 inducer, decreased pexidartinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 33% and 65%, respectively. The effect of coadministration with a moderate CYP450 3A4 inducer on pexidartinib pharmacokinetics is unknown.

MANAGEMENT: The use of pexidartinib with strong CYP450 3A4 inducers is not recommended.

ADJUST DOSING INTERVAL: The presence of food may increase the absorption and toxicity of pexidartinib. Administration of pexidartinib with a high-fat meal increased peak plasma concentration (Cmax) and systemic exposure (AUC) by 100% and prolonged the time to reach peak plasma concentration (Tmax) by 2.5 hours.

GENERALLY AVOID: Grapefruit or grapefruit juice may increase the plasma concentration and risk of adverse effects of pexidartinib, including potentially fatal hepatotoxicity. The mechanism is inhibition of CYP450 3A4-mediated metabolism of pexidartinib by certain compounds present in grapefruits. Concomitant administration of itraconazole, a strong CYP450 3A4 inhibitor, increased pexidartinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 48% and 70%, respectively.

MANAGEMENT: Pexidartinib should be administered on an empty stomach, at least one hour before or two hours after a meal or snack. Consumption of grapefruit or grapefruit juice should generally be avoided during pexidartinib therapy. If concomitant use is unavoidable, the dose of pexidartinib should be reduced according to the manufacturer's recommendations. If concomitant use of grapefruit or grapefruit juice is discontinued, the dose of pexidartinib may be increased (after 3 plasma half-lives of a strong CYP450 3A4 inhibitor) to the dose that was used prior to consumption of grapefruit or grapefruit juice.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.