Drug Interactions between amoxicillin / clarithromycin / omeprazole and nirogacestat

GENERALLY AVOID: Coadministration with potent and moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentration and pharmacologic effects of nirogacestat, which is primarily metabolized by the isoenzyme. Drug interaction studies have shown that coadministration with the potent CYP450 3A4 inhibitor itraconazole increased the systemic exposure (AUC) and peak plasma concentration (Cmax) of a single 100 mg dose of nirogacestat by 8.2-fold and 2.5-fold, respectively. Administration of multiple doses of nirogacestat (150 mg twice daily) with the potent CYP450 3A4 inhibitors itraconazole, ketoconazole, and clarithromycin is predicted to increase the AUC of nirogacestat by 6.33-fold, 5.19-fold, and 3.46-fold, respectively. In addition, coadministration of multiple doses of nirogacestat (150 mg twice daily) with the moderate CYP450 3A4 inhibitors erythromycin and fluconazole are predicted to increase the AUC of nirogacestat by 2.73-fold and 3.18-fold, respectively. Increased systemic exposure to nirogacestat may increase the risk of adverse effects including diarrhea, ovarian toxicity, hepatotoxicity, electrolyte abnormalities, and non-melanoma skin cancers.

MANAGEMENT: According to the manufacturer, concomitant use of nirogacestat with potent and moderate CYP450 3A4 inhibitors should be avoided.

GENERALLY AVOID: Concurrent administration of agents that increase gastric pH such as proton pump inhibitors (PPIs), histamine type 2 (H2)-receptor antagonists, or antacids may decrease the plasma concentrations of nirogacestat. According to the manufacturer, nirogacestat is poorly soluble at a pH of 6 or more. Reduced therapeutic efficacy may occur.

MANAGEMENT: Coadministration of nirogacestat with PPIs, H2-receptor antagonists, or antacids is not recommended. If coadministration with a gastric acid reducing agent is considered clinically necessary, the manufacturer advises administration of antacids either 2 hours before or after nirogacestat.

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.