Drug Interactions between nilotinib and zanubrutinib

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of nilotinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Because nilotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of nilotinib. The mechanism of interaction is unknown. Compared to the fast state, nilotinib systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high-fat meal. Because nilotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

MANAGEMENT: Patients treated with nilotinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. In addition, no food should be consumed for at least 2 hours before and 1 hour after a nilotinib dose.

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the plasma concentrations of zanubrutinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. When zanubrutinib was coadministered with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily), zanubrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased 157% and 278%, respectively, in healthy volunteers. Data evaluating coadministration of zanubrutinib, in patients with B-cell lymphoma, and several other known CYP450 3A4 inhibitors have been reported. When zanubrutinib was coadministered with another CYP450 3A4 inhibitor, clarithromycin (250 mg twice daily), zanubrutinib Cmax and AUC increased 101% and 92%, respectively. The moderate CYP450 3A4 inhibitor diltiazem (180 mg once daily) increased both zanubrutinib Cmax and AUC increased by 62%. Another moderate CYP450 3A4 inhibitor, fluconazole (400 mg once daily), increased zanubrutinib Cmax and AUC 81% and 88%, respectively. Clinical data for less potent inhibitors are not available. In general, the effects of grapefruit products are concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased zanubrutinib exposure may potentiate the risk of toxicities such as hemorrhage, infection, cytopenias, malignancies, and serious cardiac arrhythmias, primarily atrial fibrillation and atrial flutter.

Food does not affect the oral bioavailability of zanubrutinib. No clinically significant differences in zanubrutinib Cmax or AUC were observed following administration of a high-fat meal (approximately 1000 calories; 50% from fat) in healthy subjects.

MANAGEMENT: Zanubrutinib may be administered with or without food. Patients should avoid consumption of grapefruit, grapefruit juice, Seville oranges (a citrus relative of the grapefruit), and Seville orange juice during treatment with zanubrutinib. Close clinical monitoring for development of zanubrutinib-related toxicities, dosage adjustments, and/or withholding treatment in accordance with product labeling is advised. Additional consultation with individual package labeling, as well as relevant institutional protocols, may be advisable for further guidance.