Drug Interaction Report

GENERALLY AVOID: Coadministration of ledipasvir and simeprevir may significantly increase the plasma concentrations of both drugs. The proposed mechanism is ledipasvir inhibition of the OATP1B1-mediated hepatic uptake of simeprevir and, conversely, simeprevir inhibition of the P-glycoprotein-mediated intestinal efflux of ledipasvir. When ledipasvir 30 mg once daily was administered concomitantly with simeprevir 150 mg once daily to 22 healthy volunteers, mean simeprevir peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 161% and 169%, respectively, while mean ledipasvir Cmax and AUC increased by 81% and 92%, respectively. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions including rash and photosensitivity.

MANAGEMENT: Concomitant use of ledipasvir-sofosbuvir with simeprevir is not recommended.

ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of simeprevir, although the type of food does not seem to matter. In healthy study subjects, administration of simeprevir after a high-fat, high-caloric (928 kcal) breakfast increased systemic exposure (AUC) by 61% and delayed absorption by 1 hour, while administration after a normal caloric (533 kcal) breakfast increased AUC by 69% and delayed absorption by 1.5 hours.

MANAGEMENT: To ensure maximal oral absorption, simeprevir should be administered with food.