Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of zanubrutinib, which is primarily metabolized by the isoenzyme. When zanubrutinib was coadministered with multiple doses of the potent CYP450 3A4 inducer rifampin, zanubrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased 92% and 93%, respectively, in healthy volunteers. Reduction in zanubrutinib plasma concentration may lead to reduced zanubrutinib efficacy.

MANAGEMENT: Due to the potential for reduced pharmacologic effects, concomitant use of zanubrutinib with potent CYP450 3A4 inducers should generally be avoided.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivosidenib. 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. Pharmacokinetic data are available for the potent CYP450 3A4 inhibitor, itraconazole, and the moderate inhibitor, fluconazole. When a single 250 mg dose of ivosidenib was administered with itraconazole 200 mg once daily for 18 days, ivosidenib systemic exposure (AUC) increased to 269% of control, with no change in peak plasma concentration (Cmax). Based on physiologically-based pharmacokinetic modeling, coadministration of a 500 mg dose of ivosidenib with fluconazole (dosed to steady-state) is predicted to increase ivosidenib single-dose AUC to 173% of control, while multiple-dosing of both is predicted to increase ivosidenib steady-state Cmax and AUC to 152% and 190% of control, respectively. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (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 exposure to ivosidenib may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death.

GENERALLY AVOID: Coadministration with a high-fat meal may increase the plasma concentrations of ivosidenib. According to the product labeling, administration of a single dose with a high-fat meal (approximately 900 to 1000 calories; 500 to 600 calories in fat, 250 calories in carbohydrate, 150 calories in protein) increased ivosidenib Cmax and AUC by 98% and 25%, respectively, in healthy study subjects.

MANAGEMENT: Ivosidenib may be administered with or without food, but should not be administered with a high-fat meal. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with ivosidenib.

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.