Drug Interaction Report

GENERALLY AVOID: Coadministration with inhibitors of the hepatic influx transporters organic anion transporting polypeptides (OATP) 1B1 and 1B3 may increase the plasma concentrations and adverse effects of brincidofovir. In clinical studies, coadministration with a single 600 mg oral dose of the OATP1B1 and 1B3 inhibitor cyclosporine increased the mean systemic exposure (AUC) and peak plasma concentration (Cmax) of brincidofovir by 374% and 269%, respectively.

MANAGEMENT: The manufacturer advises that, where possible, coadministration of brincidofovir with OATP1B1 or 1B3 inhibitors should be avoided and alternative medicines considered. However, if concomitant use is necessary, administration of the OATP1B1 or 1B3 inhibitor should be postponed by at least 3 hours after the administration of brincidofovir. Patients should also be closely monitored for brincidofovir-related adverse reactions such as elevations in hepatic transaminases and bilirubin, diarrhea, nausea, vomiting, and abdominal pain.

GENERALLY AVOID: Coadministration with potent or moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of encorafenib, which is primarily metabolized by the isoenzyme. When a single 50 mg dose of encorafenib (equivalent to 0.1 times the recommended dose) was administered with posaconazole, a potent CYP450 3A4 inhibitor, encorafenib peak plasma concentration (Cmax) increased by 68% and systemic exposure (AUC) increased by 3-fold. When the same dose of encorafenib was administered with diltiazem, a moderate CYP450 3A4 inhibitor, encorafenib Cmax increased by 45% and AUC increased by 2-fold. Increased exposure to encorafenib may increase the risk of serious and life-threatening adverse effects such as hemorrhage, uveitis, QT prolongation, hepatotoxicity, dermatologic reactions, and new malignancies.

MANAGEMENT: Concomitant use of encorafenib with grapefruit or grapefruit juice should generally be avoided. If coadministration is required, the manufacturer recommends reducing the encorafenib dose to one-third of the dose used prior to addition of a potent CYP450 3A4 inhibitor or one-half of the dose used prior to addition of a moderate CYP450 3A4 inhibitor. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, the encorafenib dose that was taken prior to initiating the inhibitor may be resumed.

ADJUST DOSING INTERVAL: Administration with food decreases the oral bioavailability of brincidofovir. According to the product labeling, administration of brincidofovir tablets with a low-fat meal (approximately 400 calories, 25% of calories from fat) was associated with a reduction in the systemic exposure (AUC) and peak plasma concentration (Cmax) of brincidofovir by 31% and 49%, respectively, compared to administration under fasting. However, no clinically meaningful changes in intracellular concentrations of cidofovir diphosphate were observed. The effect of food on the oral suspension formulation has not been evaluated.

MANAGEMENT: Brincidofovir oral tablets and suspension should be taken on an empty stomach. If necessary, the oral tablets may be taken with a low-fat meal.