Drug Interaction Report

GENERALLY AVOID: Coadministration with moderate to potent CYP450 3A4 inducers may significantly decrease the plasma concentration and pharmacologic effects of nirogacestat, which is primarily metabolized by the isoenzyme. Coadministration of multiple doses of nirogacestat (150 mg twice daily) with the potent CYP450 3A4 inducer rifampin is predicted to decrease the systemic exposure (AUC) of nirogacestat by 85%. In addition, administration of multiple doses of nirogacestat (150 mg twice daily) with the moderate CYP450 3A4 inducer efavirenz is predicted to decrease the AUC of nirogacestat by 67%. Reduced therapeutic efficacy of nirogacestat may occur.

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

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 may reduce as well as delay the absorption of dabrafenib. In study subjects, administration of dabrafenib with a high-fat meal decreased peak plasma concentration (Cmax) and systemic exposure (AUC) by 51% and 31%, respectively, and delayed median Tmax by approximately 3.6 hours compared to administration in the fasted state.

MANAGEMENT: Dabrafenib should be taken at least 1 hour before or 2 hours after a meal.