Drug Interactions between elbasvir / grazoprevir and tacrolimus

MONITOR: Coadministration with elbasvir-grazoprevir may increase the blood concentrations of tacrolimus. The proposed mechanism is inhibition of the CYP450 3A4-mediated metabolism of tacrolimus by grazoprevir, a weak inhibitor of the isoenzyme. In 16 study subjects, administration of a single 2 mg dose of tacrolimus during treatment with elbasvir-grazoprevir 50 mg-200 mg once daily increased tacrolimus systemic exposure (AUC) and trough plasma concentration (Cmin) by 43% and 70%, respectively, compared to administration of tacrolimus alone. Elbasvir-grazoprevir also decreased tacrolimus peak plasma concentration (Cmax) by 40%. In contrast, the pharmacokinetics of elbasvir and grazoprevir were not significantly affected by tacrolimus.

MANAGEMENT: Given the narrow therapeutic index and the large interindividual variability in the pharmacokinetics of tacrolimus, caution is advised if the drug is used in combination with elbasvir-grazoprevir. Renal function and tacrolimus blood levels should be monitored more closely whenever elbasvir-grazoprevir is added to or discontinued from therapy, and the tacrolimus dosage adjusted as necessary. Patients should be advised to contact their doctor if they experience potential signs and symptoms of tacrolimus toxicity such as fever, infection, diarrhea, tremor, headache, fatigue, lethargy, and changes in motor function, mental status, or sensory function.