Drug Interactions between Delstrigo and encorafenib

CONTRAINDICATED: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of doravirine, which is primarily metabolized by the isoenzyme. When a single 100 mg dose of doravirine was administered with the potent CYP450 3A4 inducer rifampin (600 mg once daily) in 10 study subjects, doravirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (C24hr) decreased by an average of 57%, 88% and 97%, respectively, compared to doravirine administered alone. Reduced efficacy of doravirine may occur.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, concomitant use of doravirine with potent CYP450 3A4 inducers is considered contraindicated. At least a 4-week cessation period is recommended prior to initiation of doravirine treatment.

MONITOR: Coadministration with encorafenib may increase the plasma concentrations of drugs that are substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic cation transporter (OCT2), organic anion transporter (OAT1, OAT3), organic anion transporting polypeptide (OATP1B1, OATP1B3), or uridine diphosphate glucuronosyltransferase (UGT) 1A1. In in vivo studies, encorafenib has been shown to be an inhibitor of OATP1B1, 1B3, and BCRP. In vitro studies have demonstrated it to be an inhibitor of OCT2, OAT1, OAT3, and P-gp at expected clinical concentrations as well as a potent, reversible inhibitor of UGT1A1. Administration of a single dose of rosuvastatin, an OATP1B1, OATP1B3 and BCRP substrate, after repeated administration of encorafenib 450 mg once daily and binimetinib 45 mg twice daily, resulted in increased systemic exposure (AUC) and peak plasma concentration (Cmax) of rosuvastatin by approximately 1.6 fold and 2.7 fold respectively.

MANAGEMENT: Caution is advised if encorafenib must be used concomitantly with drugs that are substrates of the affected transporters or UGT1A1, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever encorafenib is added to or withdrawn from therapy.