Drug Interactions between elbasvir / grazoprevir and rifampin

CONTRAINDICATED: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of elbasvir and grazoprevir, both of which are substrates of the isoenzyme. In 10 study subjects, administration of elbasvir 50 mg once daily with efavirenz 600 mg once daily decreased elbasvir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 45%, 54% and 59%, respectively, compared to administration of elbasvir alone. Likewise, when grazoprevir 200 mg once daily and efavirenz 600 mg once daily were given together to 12 study subjects, grazoprevir Cmax, AUC and Cmin decreased by 87%, 83% and 69%, respectively. Efavirenz is generally considered a moderate inducer of CYP450 3A4. More potent inducers such as carbamazepine or phenytoin may interact to an even greater extent.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of elbasvir-grazoprevir with efavirenz or potent CYP450 3A4 inducers is considered contraindicated.

CONTRAINDICATED: The plasma concentrations of grazoprevir may increase significantly during acute coadministration with rifampin, but decreases after chronic coadministration. The proposed mechanism is rifampin inhibition of organic anion transporting polypeptide (OATP) 1B1-mediated hepatic uptake of grazoprevir initially, followed by induction of CYP450 3A4-mediated metabolism after multiple-dosing. In 12 study subjects, administration of a single 200 mg dose of grazoprevir with a single 600 mg intravenous dose of rifampin resulted in greater than 10-fold increases in grazoprevir peak plasma concentration (Cmax) and systemic exposure (AUC) compared to administration of grazoprevir alone. A single 600 mg oral dose of rifampin administered during multiple-dosing of grazoprevir 200 mg once daily increased the Cmax and AUC of grazoprevir by 6.5- and 8.4-fold, respectively. By contrast, when grazoprevir 200 mg and rifampin 600 mg were both given orally once daily, grazoprevir Cmax and AUC were not significantly altered, but trough plasma concentration (Cmin) was reduced by 90%. High plasma levels of grazoprevir may increase the risk of adverse effects such as alanine aminotransferase (ALT) elevations, whereas low trough levels may reduce viral susceptibility and increase the risk of resistance development. Rifampin 600 mg given orally or intravenously did not have clinically relevant effects on the pharmacokinetics of a single 50 mg dose of elbasvir.

MANAGEMENT Concomitant use of elbasvir-grazoprevir with rifampin is considered contraindicated.