Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 may 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.

MANAGEMENT: Caution is advised if ibrutinib is prescribed in combination with CYP450 3A4 inhibitors. Patients should be closely monitored for signs of ibrutinib toxicity such as myelosuppression, bleeding, infection, and renal impairment. Dosage reduction in accordance with ibrutinib product labeling may be necessary if an interaction is suspected.

GENERALLY AVOID: Coadministration with grapefruit, grapefruit juice, or Seville oranges may significantly increase the plasma concentrations of ibrutinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Pharmacokinetic modeling suggests that other moderate CYP450 3A4 inhibitors such as diltiazem and erythromycin may increase ibrutinib systemic exposure (AUC) 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.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of ibrutinib. The mechanism of interaction is unknown. According to the product labeling, administration with food increases ibrutinib exposure approximately 2-fold compared to administration after overnight fasting.

MANAGEMENT: Patients treated with ibrutinib should avoid consumption of Seville oranges, grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ibrutinib should be taken once daily at approximately the same time each day.