Drug Interaction Report

Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of doravirine, which is primarily metabolized by the isoenzyme. In 10 study subjects, administration of a single 50 mg dose of doravirine with the potent CYP450 3A4 inhibitor ritonavir (100 mg twice daily) increased doravirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (C24hr) by an average of 31%, 254% and 191%, respectively, compared to administration of doravirine alone. When a single 100 mg dose of doravirine was administered with ketoconazole 400 mg once daily in 10 study subjects, doravirine Cmax, AUC and C24hr increased by an average of 25%, 206% and 175%, respectively. These changes are not considered clinically significant.

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.