Drug Interactions between ubrogepant and Vosevi

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.

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4, breast cancer resistance protein (BCRP), and/or P-glycoprotein (P-gp) may increase the plasma concentrations of ubrogepant based on in vivo and in vitro data. The proposed mechanism involves enhanced oral bioavailability as well as reduced clearance of ubrogepant due to inhibition of CYP450 3A4-mediated metabolism and BCRP/P-gp-mediated efflux in the intestine and liver. When ubrogepant was administered with the potent CYP450 3A4 inhibitor ketoconazole during in vivo studies, ubrogepant peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 5.3- and 9.7-fold, respectively. When administered with the moderate CYP450 3A4 inhibitor verapamil, ubrogepant Cmax and AUC increased by 2.8- and 3.5-fold, respectively. Dedicated drug interaction studies have not been conducted to assess concomitant use of ubrogepant with weak CYP450 3A4 inhibitors and inhibitors of BCRP or P-gp transporters. Ubrogepant exposure is not expected to increase by more than 2-fold when used with weak CYP450 3A4 inhibitors per a conservative prediction from the manufacturer.

MANAGEMENT: The recommended dose of ubrogepant is 50 mg during concomitant treatment with weak CYP450 3A4 inhibitors and/or inhibitors of BCRP or P-gp. If needed, a second 50 mg ubrogepant dose may be administered at least 2 hours after the initial dose.

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4, breast cancer resistance protein (BCRP), and/or P-glycoprotein (P-gp) may increase the plasma concentrations of ubrogepant based on in vivo and in vitro data. The proposed mechanism involves enhanced oral bioavailability as well as reduced clearance of ubrogepant due to inhibition of CYP450 3A4-mediated metabolism and BCRP/P-gp-mediated efflux in the intestine and liver. When ubrogepant was administered with the potent CYP450 3A4 inhibitor ketoconazole during in vivo studies, ubrogepant peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 5.3- and 9.7-fold, respectively. When administered with the moderate CYP450 3A4 inhibitor verapamil, ubrogepant Cmax and AUC increased by 2.8- and 3.5-fold, respectively. Dedicated drug interaction studies have not been conducted to assess concomitant use of ubrogepant with weak CYP450 3A4 inhibitors and inhibitors of BCRP or P-gp transporters. Ubrogepant exposure is not expected to increase by more than 2-fold when used with weak CYP450 3A4 inhibitors per a conservative prediction from the manufacturer.

MANAGEMENT: The recommended dose of ubrogepant is 50 mg during concomitant treatment with weak CYP450 3A4 inhibitors and/or inhibitors of BCRP or P-gp. If needed, a second 50 mg ubrogepant dose may be administered at least 2 hours after the initial dose.