Drug Interaction Report

MONITOR: Coadministration with inducers of CYP450 3A4, particularly those that can also induce uridine diphosphate glucuronosyltransferase (UGT) 1A1, may decrease the plasma concentrations of bictegravir. According to the product labeling, bictegravir is a substrate of both CYP450 3A4 and UGT1A1; however, the extent to which each enzymatic pathway contributes to the metabolic clearance of bictegravir has not been reported. In healthy study subjects, administration of a single 75 mg dose of bictegravir during treatment with rifampin 600 mg once daily decreased mean bictegravir peak plasma concentration (Cmax) and systemic exposure (AUC) by 28% and 75%, respectively, compared to administration of bictegravir alone. When bictegravir 75 mg once daily was coadministered with rifabutin 300 mg once daily, mean bictegravir Cmax, AUC and trough plasma concentration (Cmin) decreased by 20%, 38% and 56%, respectively. These results are consistent with the fact that rifampin is a more potent inducer of CYP450 3A4 than rifabutin. Rifampin is also a known inducer of UGT1A1. The interaction has not been studied with other, less potent inducers than rifampin and rifabutin.

MANAGEMENT: The potential for diminished pharmacologic effects of bictegravir should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

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.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.