Drug Interactions between encorafenib and sofosbuvir / velpatasvir / voxilaprevir

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 isoenzymes may decrease the plasma concentrations of velpatasvir, which has been shown in vitro to be metabolized by CYP450 2B6, 2C8, and 3A4. The interaction has been studied with efavirenz, a moderate CYP450 2B6 and 3A4 inducer. In 14 healthy volunteers, administration of sofosbuvir-velpatasvir 400 mg -100 mg once daily with efavirenz/emtricitabine/tenofovir disoproxil fumarate 600 mg/200 mg/300 mg once daily decreased mean velpatasvir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 47%, 53% and 57%, respectively, compared to administration of sofosbuvir-velpatasvir alone. No clinically relevant pharmacokinetic changes were observed for sofosbuvir or its predominant circulating metabolite, GS-331007.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of sofosbuvir-velpatasvir with potent or moderate CYP450 inducers is not recommended.

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever encorafenib is added to or withdrawn from therapy.

MONITOR: Coadministration with inhibitors of organic anion transporting polypeptides (OATP) 1B1 and/or 1B3 may increase the plasma concentrations of voxilaprevir, which is a substrate of the hepatic uptake transporters. When a single 100 mg dose of voxilaprevir was administered with a single 600 mg dose of the potent OATP 1B1/1B3 inhibitor cyclosporine (n=24), mean voxilaprevir peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 19.0- and 9.4-fold, respectively. Inhibition of P-glycoprotein (P-gp)- and breast cancer resistance protein (BCRP)-mediated intestinal transport and CYP450 3A4-mediated metabolism of voxilaprevir may also contribute to the overall interaction with cyclosporine. The safety of such high levels of voxilaprevir has not been established.

MANAGEMENT: Caution and monitoring are advised when voxilaprevir is used with OATP 1B1 or 1B3 inhibitors.

MONITOR: Coadministration with inhibitors of organic anion transporting polypeptides (OATP) 1B1 and/or 1B3 may increase the plasma concentrations of voxilaprevir, which is a substrate of the hepatic uptake transporters. When a single 100 mg dose of voxilaprevir was administered with a single 600 mg dose of the potent OATP 1B1/1B3 inhibitor cyclosporine (n=24), mean voxilaprevir peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 19.0- and 9.4-fold, respectively. Inhibition of P-glycoprotein (P-gp)- and breast cancer resistance protein (BCRP)-mediated intestinal transport and CYP450 3A4-mediated metabolism of voxilaprevir may also contribute to the overall interaction with cyclosporine. The safety of such high levels of voxilaprevir has not been established.

MANAGEMENT: Caution and monitoring are advised when voxilaprevir is used with OATP 1B1 or 1B3 inhibitors.