Drug Interaction Report

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of ixabepilone, which is primarily metabolized by the isoenzyme. According to the manufacturer, coadministration of ixabepilone with the potent CYP450 3A4 inducer rifampin decreased ixabepilone systemic exposure (AUC) by 43% compared to administration of ixabepilone alone. Reduced efficacy of ixabepilone may occur. However, the extent to which less potent CYP450 3A4 inducers interact with ixabepilone is unknown.

MANAGEMENT: The potential for diminished pharmacologic effects of ixabepilone should be considered during coadministration with CYP450 3A4 inducers. Caution is advised if they are used with ixabepilone, and alternative treatments may be required if an interaction is suspected.

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: Grapefruit juice may increase the plasma concentrations of ixabepilone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients treated with ixabepilone should avoid the consumption of grapefruit or grapefruit juice.