Drug Interactions between boceprevir and tacrolimus

ADJUST DOSE: Coadministration with the hepatitis C virus (HCV) NS3/4A protease inhibitors, boceprevir and telaprevir, may significantly increase the plasma concentrations of tacrolimus. The proposed mechanism is inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme responsible for the metabolic clearance of tacrolimus. Enhanced tacrolimus oral bioavailability due to inhibition of intestinal P-glycoprotein efflux transporter may also contribute. In 9 study subjects, administration of a single 0.5 mg dose of tacrolimus during treatment with telaprevir 750 mg every 8 hours for 11 days increased the tacrolimus peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 2.3- and 17.6-fold, respectively, compared to administration of a single 2 mg dose of tacrolimus alone. Adjusted for dose, tacrolimus Cmax and AUC increased by 9.4- and 70.3-fold, respectively, during coadministration with telaprevir. When a single 0.5 mg dose of tacrolimus was coadministered with boceprevir 800 mg three times a day for 7 days, tacrolimus Cmax increased by 9.9-fold and AUC increased by 17.1-fold. Clinically, these changes may result in an increased risk of nephro- and neurotoxicity, as well as other adverse effects associated with tacrolimus such as malignancies, infections, diabetes, hyperkalemia, hypertension, and QT prolongation. Tacrolimus had no effect on the pharmacokinetics of boceprevir.

MANAGEMENT: Caution is advised when tacrolimus is used with boceprevir or telaprevir. Dosage reduction and/or prolongation of the dosing interval for tacrolimus will likely be required. Tacrolimus blood levels and renal function should be checked frequently and the dosage adjusted accordingly, particularly following initiation or discontinuation of the HCV NS3/4A protease inhibitor. Patients should be advised to seek medical attention if they experience adverse effects such as fever, infection, diarrhea, tremor, decreased urination, headache, paraesthesia, seizures, and changes in motor function, mental status, or sensory function. Some authorities recommend against the use of telaprevir in organ transplant candidates or patients.