Drug Interaction Report

MONITOR: Coadministration of pexidartinib with moderate CYP450 3A4 inducers may decrease the plasma concentrations and therapeutic effects of pexidartinib. The proposed mechanism is induction of CYP450 3A4, the isoenzyme primarily 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. No data are available regarding the effects that other, less potent CYP450 3A4 inducers may have on the pharmacokinetics of pexidartinib.

MANAGEMENT: Caution is advised if pexidartinib is used with moderate CYP450 3A4 inducers. It is unknown if pexidartinib will require a dosage adjustment if coadministered with a moderate CYP450 3A4 inducer. Clinical and laboratory monitoring of pexidartinib should be considered whenever a moderate CYP450 3A4 inducer is added to or withdrawn from therapy. Patients should be monitored for diminished therapeutic effects.

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: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.