Drug Interactions between dabigatran and sofosbuvir / velpatasvir / voxilaprevir

MONITOR CLOSELY: Coadministration of dabigatran etexilate with sofosbuvir/velpatasvir/voxilaprevir may significantly increase the plasma concentrations of dabigatran. The proposed mechanism is inhibition of the P-glycoprotein (P-gp)-mediated renal tubular secretion of dabigatran by velpatasvir and voxilaprevir, both of which are inhibitors of the transporter. In 36 study subjects, administration of a single 75 mg dose of dabigatran etexilate with sofosbuvir/velpatasvir/voxilaprevir 400 mg/100 mg/100 mg plus voxilaprevir 100 mg once daily increased mean dabigatran peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 2.9- and 2.6-fold, respectively, compared to administration of dabigatran etexilate alone.

MANAGEMENT: Caution is advised if dabigatran is used in combination with sofosbuvir/velpatasvir/voxilaprevir. Pharmacologic response to dabigatran should be monitored more closely whenever sofosbuvir/velpatasvir/voxilaprevir is added to or withdrawn from therapy, and the dabigatran dosage adjusted as necessary. Patients should be monitored for the development of anemia and bleeding complications during coadministration. In patients with moderate renal impairment (CrCl 30 to 50 mL/min), concomitant use with potent P-gp inhibitors can generally be expected to produce dabigatran exposure similar to that observed in severe renal impairment. Therefore, a reduction in the dabigatran dosage to 75 mg twice daily should be considered. Based on the magnitude of interaction reported, concomitant use of dabigatran with sofosbuvir/velpatasvir/voxilaprevir in patients with severe renal impairment (CrCl 15 to 30 mL/min) should probably be avoided.

MONITOR: Coadministration with inhibitors of P-glycoprotein (P-gp) such as velpatasvir may increase the bioavailability of dabigatran following oral administration of dabigatran etexilate, which is a substrate of the efflux transporter. Pharmacokinetic data are lacking.

MANAGEMENT: Pharmacologic response to dabigatran should be monitored more closely whenever a P-gp inhibitor is added to or withdrawn from therapy, and the dabigatran dosage adjusted as necessary. Patients should be monitored for the development of anemia and bleeding complications during coadministration.

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.