Drug Interaction Report

MONITOR: Theoretically, coadministration of remdesivir with potent inducers of CYP450 3A4 may decrease the plasma concentration of remdesivir, which has been shown in vitro to be a substrate of the isoenzyme. However, the potential for this interaction appears low as remdesivir's metabolism is predominantly mediated by hydrolysis via esterases in vivo, which are not significantly affected by CYP450 3A4. When a single dose of remdesivir (100 mg) was administered to healthy volunteers on carbamazepine (300 mg twice daily), remdesivir's peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 13% and 8%, respectively. One of remdesivir's metabolites (GS-704277) had no change in its Cmax or AUC, while its other metabolite (GS-441524) had a reduction in AUC of 17%.

MANAGEMENT: Caution and clinical monitoring may be advisable if remdesivir is administered concurrently with potent inducers of CYP450 3A4 as they may reduce its concentrations and effects. While clinically significant interactions are not expected, some authorities recommend avoiding concomitant use of remdesivir with potent CYP450 3A4 inducers.

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.