Drug Interactions between boceprevir and ibrutinib

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of ibrutinib, which is primarily metabolized by the isoenzyme. In 18 healthy volunteers administered a single 120 mg dose of ibrutinib alone on day 1 and a single 40 mg dose of ibrutinib on day 7 in combination with ketoconazole 400 mg daily on days 4 thru 9, there was a 29-fold increase in dose-normalized ibrutinib peak plasma concentration (Cmax) and 24-fold increase in dose-normalized systemic exposure (AUC) during treatment with ketoconazole compared to administration alone. Pharmacokinetic modeling suggests that moderate CYP450 3A4 inhibitors such as diltiazem and erythromycin may increase the AUC of ibrutinib by 6- to 9-fold under fasting condition. The safety and efficacy of these exposures are unknown. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 to 1400 mg) given for 28 days, which yielded single dose AUC values that were approximately 50% greater than steady-state exposures seen at the highest indicated dose of 560 mg.

MANAGEMENT: The use of ibrutinib in combination with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics should generally be avoided, particularly those that are intended for chronic administration. Some authorities recommend avoiding concomitant use of ibrutinib during and for 2 weeks after treatment with itraconazole. Alternative agents with no or minimal CYP450 3A4 inhibitory potential are recommended whenever possible. If no alternatives exist and the CYP450 3A4 inhibitor is used short-term for 7 days or less, consider interrupting or delaying initiation of ibrutinib treatment until therapy with the inhibitor is complete. Patients should be closely monitored for signs of ibrutinib toxicity such as myelosuppression, bleeding, infection, and renal impairment.

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