Drug Interactions between amoxicillin / clarithromycin / omeprazole and talazoparib

ADJUST DOSE: Coadministration with inhibitors of P-glycoprotein (P-gp) may increase the plasma concentrations of talazoparib, which has been shown in vitro to be a substrate of the efflux transporter. In a drug-drug interaction study in patients with advanced solid tumors, compared with a single talazoparib dose (0.5 mg), multiple daily doses of the P-gp inhibitor itraconazole (100 mg twice daily) with a single dose of talazoparib (0.5 mg) increased the talazoparib total exposure and peak plasma concentration by 56% and 40%, respectively. In addition, population pharmacokinetic analysis has shown that administration of talazoparib with the P-gp inhibitors amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil resulted in an approximate 45% increase in talazoparib exposure and an increase in the rate of talazoparib dose reduction. In contrast, coadministration with the P-gp inhibitors azithromycin, atorvastatin, diltiazem, felodipine, fluvoxamine, and quercetin increased talazoparib exposure by just 8%.

MANAGEMENT: Concomitant use of talazoparib with amiodarone, carvedilol, clarithromycin, itraconazole, or verapamil should preferably be avoided. If coadministration is required, talazoparib should be initiated at a reduced dosage of 0.75 mg once daily. Patients should be closely monitored for adverse effects such as myelosuppression and myelodysplastic syndrome/acute myeloid leukemia, and further dosage adjustments made or treatment withheld as needed in accordance with the product labeling. After 3 to 5 half-lives following discontinuation of the P-gp inhibitor, the talazoparib dosage may be increased to that used prior to initiation of the P-gp inhibitor.

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.