Drug Interactions between amoxicillin / clarithromycin / vonoprazan and zanubrutinib

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of zanubrutinib, which is primarily metabolized by the isoenzyme. 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. Another potent CYP450 3A4 inhibitor, clarithromycin (250 mg twice daily), is predicted to increase zanubrutinib Cmax and AUC by 175% and 183%, respectively, based on pharmacokinetic modeling. 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).

MANAGEMENT: The manufacturer recommends reducing the dosage of zanubrutinib to 80 mg once daily when coadministered with potent CYP450 3A4 inhibitors. Patients should be closely monitored for development of zanubrutinib-related toxicities, and further dosage adjustments made or treatment withheld as needed in accordance with the product labeling. Following discontinuation of the CYP450 3A4 inhibitor, the previous dosage of zanubrutinib should be resumed.

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of zanubrutinib, which is primarily metabolized by the isoenzyme. 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 other known 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. Simulations using fasted conditions suggest that mild CYP450 3A4 inhibitors may increase the AUC of zanubrutinib by <1.5-fold.

MANAGEMENT: Caution is advised when zanubrutinib is used with CYP450 3A4 inhibitors. Patients should be monitored for increased adverse effects such as rash, diarrhea, constipation, cough, hemorrhage, infection, cytopenias, and atrial fibrillation or flutter, and the zanubrutinib dosage adjusted as necessary.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.