Drug Interaction Report

GENERALLY AVOID: Coadministration with gemfibrozil may significantly increase the plasma concentrations of bexarotene. The exact mechanism of interaction is unknown. In an analysis of the pharmacokinetic data acquired during two clinical studies of bexarotene treatment in patients with cutaneous T-cell lymphoma, investigators found that mean plasma bexarotene concentrations (dose-normalized) were more than 5 times higher with concomitant gemfibrozil therapy than without. Plasma metabolite chromatography profiles were consistent with an inhibition of the oxidative metabolism of bexarotene by gemfibrozil, although the exact CYP450 isoenzyme involved has not been elucidated. The combination has also been reported to increase serum triglyceride levels in some patients. By contrast, concomitant fenofibrate did not appear to affect bexarotene pharmacokinetics; however, data were insufficient to provide an adequate assessment.

MANAGEMENT: The use of bexarotene in combination with gemfibrozil should generally be avoided.

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.