Drug Interaction Report

GENERALLY AVOID: Coadministration with cobicistat may increase plasma concentrations of elbasvir and grazoprevir. The proposed mechanism is cobicistat-mediated inhibition of CYP450 3A4 and the hepatic uptake OATP1B transporter. Elbasvir and grazoprevir are both substrates of CYP450 3A4 and grazoprevir is also a substrate of OATP1B. High plasma levels of grazoprevir may increase the risk of adverse effects such as alanine aminotransferase (ALT) elevations. The interaction has been studied with the fixed-dose combination antiretroviral regimen elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (Stribild) and is also expected with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya). Administration of elbasvir-grazoprevir 50 mg-100 mg once daily with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (150 mg/150 mg/200 mg/300 mg once daily) (n=21) increased grazoprevir peak plasma concentration (Cmax), systemic exposure (AUC), and trough plasma concentration (Cmin) by 5.36-fold, 4.59-fold, and 2.78-fold, respectively. Elbasvir Cmax, AUC, and Cmin were also increased by 2.18-fold, 1.91-fold, and 2.38-fold, respectively.

MANAGEMENT: Concomitant use of elbasvir-grazoprevir with the fixed-dose cobicistat-containing antiretroviral regimen elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or alafenamide should generally be avoided.

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of elbasvir, which is a substrate of the isoenzyme. In 10 study subjects, administration of elbasvir (50 mg once daily) with the potent CYP450 3A4 inhibitors atazanavir/ritonavir (300 mg/100 mg once daily) increased elbasvir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 4.15-fold, 4.76-fold and 6.45-fold, respectively, compared to elbasvir alone. Likewise, administration with lopinavir/ritonavir 400 mg/100 mg twice daily increased elbasvir Cmax, AUC, and Cmin by 2.87-, 3.71-, and 4.58-fold, respectively (n=10), while administration with darunavir/ritonavir 600 mg/100 mg twice daily increased elbasvir Cmax, AUC, and Cmin by 1.67-, 1.66-, and 1.82-fold, respectively (n=10). Another potent CYP450 3A4 inhibitor, ketoconazole (400 mg once daily), increased the Cmax, AUC, and Cmin of a single 50 mg dose of elbasvir by 1.29-, 1.80, and 1.89-fold, respectively (n=7).

MANAGEMENT: Concomitant use of elbasvir with potent CYP450 3A4 inhibitors should generally be avoided.

Food does not appear to have clinically significant effects on the pharmacokinetics of elbasvir and grazoprevir. When a single 50 mg-100 mg dose of elbasvir-grazoprevir was administered to healthy study subjects with a high-fat meal (900 kcal; 500 kcal from fat), elbasvir peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 15% and 11%, respectively, while grazoprevir Cmax and AUC increased by 2.8- and 1.5-fold, respectively, compared to administration under fasting conditions. According to the product labeling, elbasvir-grazoprevir may be administered with or without food.