Drug Interaction Report

GENERALLY AVOID: Coadministration with nirogacestat may increase the plasma concentrations and therapeutic effects of drugs that are substrates of CYP450 3A4. The interaction may be significant for sensitive CYP450 3A4 substrates or those that demonstrate a narrow therapeutic index. The proposed mechanism is decreased clearance due to nirogacestat-mediated inhibition of CYP450 3A4. Concomitant use of the sensitive CYP450 3A4 substrate midazolam with multiple doses of nirogacestat (150 mg twice daily) is predicted to increase the systemic exposure (AUC) and peak plasma concentration (Cmax) of midazolam by 2.07-fold and 1.77-fold, respectively.

MANAGEMENT: According to the manufacturer, concomitant use of nirogacestat with sensitive CYP450 3A4 substrates or those that demonstrate a narrow therapeutic index (e.g., ergot alkaloids, colchicine, fentanyl, macrolide immunosuppressants, midazolam, triazolam, vinca alkaloids) is not recommended.

GENERALLY AVOID: Grapefruit, grapefruit juice, Seville oranges, and starfruit may significantly increase the plasma concentrations and pharmacologic effects of nirogacestat. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. 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. The interaction has not been studied with grapefruit, Seville oranges, or starfruit. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (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 systemic exposure to nirogacestat may increase the risk of adverse effects including diarrhea, ovarian toxicity, hepatotoxicity, electrolyte abnormalities, and non-melanoma skin cancers.

MANAGEMENT: Patients treated with nirogacestat should avoid consumption of grapefruit, grapefruit juice, Seville oranges, starfruit, or any supplement containing grapefruit.

ADJUST DOSING INTERVAL: Food reduces the variability in oral absorption and bioavailability of avatrombopag. According to the product labeling, avatrombopag peak plasma concentration (Cmax) and systemic exposure (AUC) were not affected when administered with either a low-fat (500 calories; 3 g fat, 15 g proteins, 108 g carbohydrates) or high-fat (918 calories; 59 g fat, 39 g proteins, 59 g carbohydrates) meal. However, the variability of avatrombopag exposure was reduced by 40% to 60% with food, and the time to reach Cmax was delayed by 0 to 2 hours relative to the fasted state.

MANAGEMENT: To ensure consistent absorption and plasma drug levels, avatrombopag should be taken with food.