Drug Interactions between rifampin and sofosbuvir / velpatasvir / voxilaprevir

GENERALLY AVOID: Coadministration with rifampin may significantly decrease the plasma concentrations of sofosbuvir and other direct-acting antiviral agents that may be given with sofosbuvir in fixed-dose combination products such as ledipasvir and velpatasvir. The proposed mechanism is induction of intestinal P-glycoprotein (P-gp)-mediated efflux by rifampin, which results in decreased oral bioavailability of the antiviral agents. Induction of CYP450 2B6, 2C8, and 3A4 may also contribute in the case of velpatasvir. In 17 healthy volunteers, administration of a single 400 mg dose of sofosbuvir during multiple dosing of rifampin 600 mg once daily reduced mean sofosbuvir peak plasma concentration (Cmax) and systemic exposure (AUC) by 77% and 72%, respectively. Likewise, administration of a single 90 mg dose of ledipasvir to 31 healthy volunteers during multiple dosing of rifampin 600 mg once daily decreased mean ledipasvir Cmax and AUC by 35% and 59%, respectively. When a single 100 mg dose of velpatasvir was given with rifampin 600 mg once daily to 12 healthy volunteers, velpatasvir Cmax decreased by 71% and AUC decreased by 82%.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of rifampin should generally be avoided during treatment with sofosbuvir, given either as a single-ingredient product or as a fixed-dose combination product with ledipasvir or velpatasvir.

CONTRAINDICATED: The plasma concentrations of voxilaprevir may increase significantly during acute coadministration with rifampin, but decreases after chronic coadministration. The proposed mechanism is rifampin inhibition of organic anion transporting polypeptide (OATP) 1B1-mediated hepatic uptake of voxilaprevir initially, followed by induction of P-glycoprotein-mediated intestinal efflux and CYP450 3A4-mediated metabolism of voxilaprevir after chronic dosing. In 24 study subjects, mean voxilaprevir peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 11.1- and 7.9-fold, respectively, after a single 100 mg dose of voxilaprevir administered with the first 600 mg dose of rifampin. Following multiple dosing of rifampin 600 mg once daily, however, mean voxilaprevir Cmax and AUC decreased by 9% and 73%, respectively.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of voxilaprevir with rifampin is considered contraindicated.

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.