Drug Interaction Report

MONITOR: Coadministration with CYP450 3A4 inducers may decrease plasma concentrations and pharmacologic effects of crizotinib, which is primarily metabolized by the isoenzyme. In study subjects, administration of a single 250 mg oral dose of crizotinib during treatment with the strong CYP450 3A4 inducer rifampin (600 mg once daily) resulted in an approximately 69% decrease in crizotinib peak plasma concentration (Cmax) and an 82% decrease in systemic exposure (AUC) compared to crizotinib administered alone. Crizotinib steady state Cmax and AUCinf decreased by 79% and 84%, respectively, following repeated coadministration of crizotinib (250 mg twice daily) and rifampin (600 mg once daily) compared to crizotinib alone. The extent to which mild to moderate CYP450 3A4 inducers may interact with crizotinib is unknown.

MANAGEMENT: Caution and clinical monitoring should be considered if CYP450 3A4 inducers such as efavirenz are used with crizotinib.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of crizotinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Because crizotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

Food has no significant effect on the gastrointestinal absorption of crizotinib. According to the product labeling, a high-fat meal reduced crizotinib peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 14%.

MANAGEMENT: Patients treated with crizotinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Crizotinib may be taken without regards to food.

ADJUST DOSING INTERVAL: Food may enhance the oral bioavailability of bexarotene. In one clinical study, bexarotene peak plasma concentration (Cmax) and systemic exposure (AUC) resulting from a 75 to 300 mg dose were 35% and 48% higher, respectively, when administered after a fat-containing meal relative to a glucose solution. In all clinical trials, patients were instructed to take bexarotene with or immediately following a meal.

Coadministration with inhibitors of CYP450 3A4 such as grapefruit juice may theoretically increase the plasma concentrations of bexarotene. In vitro studies suggest that bexarotene is metabolized by CYP450 3A4. However, concomitant administration with multiple doses of ketoconazole, a potent CYP450 3A4 inhibitor, did not alter bexarotene plasma concentrations, which would imply that bexarotene elimination is not substantially dependent on CYP450 3A4 metabolism in vivo.

MANAGEMENT: Because safety and efficacy data are based upon administration with food, bexarotene should be administered once daily with a meal. Patients may want to avoid consuming large amounts of grapefruit or grapefruit juice.