Drug Interactions between acalabrutinib and amoxicillin / clarithromycin / omeprazole

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of acalabrutinib, which is primarily metabolized by CYP450 3A enzymes to form its active metabolite, ACP-5862. In some instances, inhibition of P-glycoprotein (P-gp) may also contribute, as both acalabrutinib and ACP-5862 have been shown in vitro to be substrates of the efflux transporter. When acalabrutinib was administered with the potent CYP450 3A4 and P-gp inhibitor itraconazole (200 mg once daily for 5 days) in 17 healthy subjects, acalabrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3.9- and 5.1-fold, respectively. Increased acalabrutinib exposure may potentiate the risk of toxicities such as hemorrhage, infection, cytopenias, malignancies, and atrial fibrillation or flutter.

MANAGEMENT: Concomitant use of acalabrutinib with potent CYP450 3A4 inhibitors should generally be avoided, particularly those that are intended for chronic administration. Alternative agents with no or minimal CYP450 3A4 inhibitory potential are recommended whenever possible. If no alternatives exist and the CYP450 3A4 inhibitor is used short-term for 7 days or less, consider interrupting or delaying initiation of acalabrutinib treatment until therapy with the inhibitor is complete. If treatment is interrupted, the patient's previous dosage may be resumed after the strong inhibitor has been discontinued for at least 24 hours.

GENERALLY AVOID: Coadministration of acalabrutinib in its capsule formulation with proton pump inhibitors may significantly decrease the oral bioavailability of acalabrutinib and reduce its concentrations in plasma. The solubility of acalabrutinib is pH-dependent and decreases with increasing pH. According to the product labeling, acalabrutinib is freely soluble in water at pH below 3 and practically insoluble at pH above 6. Coadministration of acalabrutinib capsules with omeprazole 40 mg for 5 days decreased acalabrutinib systemic exposure (AUC) by 43% in healthy subjects. Due to the long-lasting effect of proton pump inhibitors, separation of dosing may not eliminate the interaction with acalabrutinib capsules. By contrast, no clinically significant differences in the pharmacokinetics of acalabrutinib were observed when the tablet formulation, which contains acalabrutinib maleate, was coadministered with the proton pump inhibitor, rabeprazole.

MANAGEMENT: No adjustments to therapy are required when using the tablet formulation containing acalabrutinib maleate. However, concomitant use of acalabrutinib capsules with proton pump inhibitors should generally be avoided. If gastric acid reducing agents are required during treatment with acalabrutinib capsules, antacids and/or H2-receptor antagonists should be considered, with dosing separated by a couple hours from acalabrutinib dosing as suggested in the manufacturer's labeling.

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.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.