Drug Interaction Report

ADJUST DOSE: Coadministration with simeprevir may increase the plasma concentrations of various statins. The proposed mechanism is simeprevir inhibition of OATP1B1-mediated hepatic uptake and/or CYP450 3A4-mediated intestinal metabolism of the affected statins. In 18 healthy study subjects, administration of a single 40 mg dose of atorvastatin in combination with simeprevir 150 mg once daily for 10 days increased mean atorvastatin peak plasma concentration (Cmax) by approximately 1.7-fold and systemic exposure (AUC) by 2.1-fold compared to atorvastatin administered alone. In addition, mean Cmax and AUC of 2-hydroxyatorvastatin increased by approximately 2.0- and 2.3-fold, respectively. Likewise, simeprevir 150 mg once daily for 7 days increased the mean Cmax of a single 10 mg dose of rosuvastatin by approximately 3.2-fold and systemic exposure (AUC) by 2.8-fold in 16 healthy study subjects. When a single 40 mg dose of simvastatin was given with simeprevir 150 mg once daily for 10 days to 18 healthy volunteers, mean Cmax and AUC of simvastatin increased by 46% and 51%, respectively, while Cmax and AUC of simvastatin acid increased by 3.0- and 1.9-fold, respectively. High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death. No data are available for lovastatin, pitavastatin and pravastatin, although they are known substrates of OATP1B1 and/or CYP450 3A4.

MANAGEMENT: The lowest dosage of affected statins should be used when prescribed in combination with simeprevir, and the dosage titrated cautiously. Alternatively, fluvastatin may be substituted, as it has been shown to have no significant interaction with simeprevir. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

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.