Drug Interactions between amiodarone and zanubrutinib

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of orally administered amiodarone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In 11 nonsmoking, healthy volunteers, grapefruit juice (300 mL with drug administration, then 3 hours and 9 hours later) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amiodarone (17 mg/kg single dose) by 84% and 50%, respectively, compared to water. Formation of the pharmacologically active metabolite, N-desethylamiodarone (N-DEA), was completely inhibited. Clinically, this interaction can lead to altered efficacy of amiodarone, since antiarrhythmic properties of amiodarone and N-DEA appear to differ. In the study, mean increases in PR and QTc intervals of 17.9% and 11.3%, respectively, were observed 6 hours postdose with water, while increases of 10.2% and 3.3%, respectively, were observed after administration with grapefruit juice.

ADJUST DOSING INTERVAL: Food increases the rate and extent of absorption of amiodarone. The mechanism appears to involve the effect of food-induced physiologic changes on drug release from its formulation. In 30 healthy volunteers, administration of a single 600 mg dose of amiodarone following a high-fat meal resulted in a Cmax and AUC that were 3.8 and 2.4 times the respective values under fasting conditions. The time to reach peak plasma concentration (Tmax) was decreased by 37%, indicating an increased rate of absorption. Mean Cmax and AUC for the active metabolite, N-DEA, also increased by 32% and 55%, respectively, but there was no change in the Tmax.

MANAGEMENT: Patients treated with oral amiodarone should avoid consumption of grapefruits and grapefruit juice. In addition, oral amiodarone should be administered consistently with regard to meals.

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 administered with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily) in clinical study subjects, zanubrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 157% and 278%, respectively. Data derived from pharmacokinetic modeling have also been reported for several additional CYP450 3A4 inhibitors. For example, the potent CYP450 3A4 inhibitor clarithromycin (250 mg twice daily) is predicted to increase zanubrutinib Cmax and AUC by 175% and 183%, respectively. The moderate CYP450 3A4 inhibitor diltiazem (60 mg three times daily) is predicted to increase zanubrutinib Cmax and AUC by 151% and 157%, respectively. Another moderate CYP450 3A4 inhibitor, erythromycin (500 mg four times daily), is predicted to increase zanubrutinib Cmax and AUC by 284% and 317%, respectively. Likewise, fluconazole 200 mg once daily is predicted to increase zanubrutinib Cmax and AUC by 179% and 177%, respectively; while fluconazole 400 mg once daily is predicted to increase zanubrutinib Cmax and AUC by 270% and 284%, respectively. 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, and Seville orange juice during treatment with zanubrutinib.