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.

ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.

MANAGEMENT: Tacrolimus should be administered at least one hour before or two hours after meals.

GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations. Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.

MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.

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.