Drug Interactions between rosuvastatin and sofosbuvir / velpatasvir / voxilaprevir

ADJUST DOSE: Coadministration with velpatasvir may significantly increase the plasma concentrations of rosuvastatin. The proposed mechanism is velpatasvir inhibition of the hepatic uptake of rosuvastatin via organic anion transporting polypeptide 1B1 (OATP1B1). Inhibition of breast cancer resistance protein (BCRP)-mediated transport may also contribute. In 18 healthy volunteers, administration of a single 10 mg dose of rosuvastatin with velpatasvir 100 mg once daily increased mean rosuvastatin peak plasma concentration (Cmax) by approximately 2.6-fold and systemic exposure (AUC) by 2.7-fold compared to rosuvastatin administered alone. By contrast, when a single 40 mg dose of pravastatin was given with velpatasvir 100 mg once daily, mean Cmax and AUC of pravastatin increased by just 28% and 35%, 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.

MANAGEMENT: Rosuvastatin should not exceed a dosage of 10 mg daily when prescribed with sofosbuvir-velpatasvir. Alternatively, fluvastatin or pravastatin may be substituted, as the former is not a substrate of OATP1B1, and the latter has been found to not interact significantly with velpatasvir. 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.

GENERALLY AVOID: Coadministration with sofosbuvir/velpatasvir/voxilaprevir may significantly increase the plasma concentrations of rosuvastatin. The proposed mechanism is inhibition of organic anion transporting polypeptide (OATP) 1B1-mediated hepatic uptake of rosuvastatin by velpatasvir and voxilaprevir. Inhibition of breast cancer resistance protein (BCRP)-mediated intestinal and hepatic transport of rosuvastatin may also contribute. When a single 10 mg dose of rosuvastatin was administered with sofosbuvir/velpatasvir/voxilaprevir 400 mg/100 mg/100 mg plus voxilaprevir 100 mg once daily to 19 healthy study subjects, mean rosuvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 18.9- and 7.4-fold, respectively. High levels of HMG-CoA reductase inhibitory activity in plasma may be 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.

MANAGEMENT: Concomitant use of rosuvastatin with sofosbuvir/velpatasvir/voxilaprevir is not recommended.

MONITOR: Coadministration with inhibitors of organic anion transporting polypeptides (OATP) 1B1 and/or 1B3 may increase the plasma concentrations of voxilaprevir, which is a substrate of the hepatic uptake transporters. When a single 100 mg dose of voxilaprevir was administered with a single 600 mg dose of the potent OATP 1B1/1B3 inhibitor cyclosporine (n=24), mean voxilaprevir peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 19.0- and 9.4-fold, respectively. Inhibition of P-glycoprotein (P-gp)- and breast cancer resistance protein (BCRP)-mediated intestinal transport and CYP450 3A4-mediated metabolism of voxilaprevir may also contribute to the overall interaction with cyclosporine. The safety of such high levels of voxilaprevir has not been established.

MANAGEMENT: Caution and monitoring are advised when voxilaprevir is used with OATP 1B1 or 1B3 inhibitors.