Drug Interactions between fosphenytoin and sofosbuvir / velpatasvir

GENERALLY AVOID: Coadministration with potent inducers of P-glycoprotein (P-gp) 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. Induction of P-gp-mediated efflux in the intestine decreases the oral bioavailability of these antiviral agents, which are substrates of the transporter. The interaction has been studied with rifampin, a potent inducer of P-gp and CYP450 isoenzymes. 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 potent P-gp inducers 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.