Drug Interaction Report

MONITOR: Coadministration with simeprevir may affect the pharmacokinetics of immunosuppressants that are substrates of the P-glycoprotein efflux transporter and/or CYP450 3A4 isoenzyme. In vivo, simeprevir mildly inhibits P-glycoprotein and intestinal CYP450 3A4, but does not affect hepatic CYP450 3A4 activity. In 14 healthy study subjects, administration of simeprevir 150 mg once daily for 7 days decreased the mean Cmax and AUC of a single 2 mg dose of tacrolimus by 24% and 17%, respectively. No data are available for everolimus or sirolimus, although they are known substrates of both P-glycoprotein and CYP450 3A4.

MANAGEMENT: No empiric dosage adjustment is required for everolimus, sirolimus, or tacrolimus when prescribed with simeprevir. However, because these agents have a narrow therapeutic index, it may be appropriate to monitor pharmacologic response and drug levels more closely following initiation or discontinuation of simeprevir, and the dosage adjusted if necessary.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of orally administered everolimus. The mechanism is inhibition of CYP450 3A4 and P-glycoprotein activity in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: Patients treated with everolimus should avoid consumption of grapefruit and grapefruit juice.

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.