Drug Interactions between atorvastatin and sofosbuvir / velpatasvir / voxilaprevir

MONITOR: Coadministration with velpatasvir may increase the plasma concentrations of the HMG-CoA reductase inhibitors atorvastatin and simvastatin. The proposed mechanism has not been delineated but may involve velpatasvir inhibition of the hepatic uptake transporter organic anion transporting polypeptide 1B (OATP1B), and the efflux transporters P-glycoprotein (P-gp), and/or breast cancer resistance protein (BCRP), of which atorvastatin and simvastatin are substrates. The interaction has not been studied specifically with all statins; data are currently available for rosuvastatin. 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: The lowest dose of atorvastatin or simvastatin should be used when prescribed with sofosbuvir-velpatasvir, and the dosage titrated cautiously. Pravastatin may be considered as a substitute. 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 DOSE: Coadministration with sofosbuvir/velpatasvir/voxilaprevir may increase the plasma concentrations of all statins including atorvastatin, fluvastatin, lovastatin, and simvastatin. The proposed mechanism is inhibition of organic anion transporting polypeptide (OATP) 1B1-mediated hepatic uptake of statins by velpatasvir and voxilaprevir. Although the interaction has not been studied specifically with atorvastatin, fluvastatin, lovastatin or simvastatin, it has been reported with other statins that are also substrates of OATP1B1. 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: Caution is advised during concomitant administration of atorvastatin, fluvastatin, lovastatin, simvastatin, or red yeast rice (which contains lovastatin) with sofosbuvir/velpatasvir/voxilaprevir. The lowest approved dosage of the statin should be used. If higher dosages are required, the lowest effective statin dosage should be prescribed based on a risk/benefit assessment.

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.