Drug Interactions between ketoconazole and nirogacestat

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.

GENERALLY AVOID: Excessive use of alcohol or products containing alcohol together with ketoconazole or levoketoconazole may potentiate the risk of liver injury. Serious hepatotoxicity has been reported with levoketoconazole. Hepatotoxicity requiring liver transplantation has been reported with the use of oral ketoconazole, of which levoketoconazole is an enantiomer. Some patients had no obvious risk factors for liver disease. In addition, use of alcohol or products containing alcohol during ketoconazole or levoketoconazole therapy may result in a disulfiram-like reaction in some patients. Symptoms of disulfiram-like reaction include flushing, rash, peripheral edema, nausea, and headache.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of ketoconazole or levoketoconazole. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Inhibition of hepatic CYP450 3A4 may also contribute. 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

When administered to healthy volunteers with a high-fat meal (875 calories; 62% fat), levoketoconazole systemic exposure (AUC) increased by 30% while peak plasma concentration (Cmax) did not change and the time to reach Cmax (Tmax) was delayed from 2 to 4 hours, compared to fasted conditions.

MANAGEMENT: Levoketoconazole may be administered with or without food. Excessive consumption of alcohol should generally be avoided during ketoconazole or levoketoconazole therapy. Patients should preferably avoid or limit consumption of grapefruit, grapefruit juice, or any supplement containing grapefruit extract during ketoconazole or levoketoconazole therapy. Patients receiving ketoconazole or levoketoconazole should be instructed to contact their doctor immediately if they experience swelling, skin rash, itching, loss of appetite, fatigue, nausea, vomiting, abdominal pain, dark colored urine, light colored stools, and/or yellowing of the skin or eyes, as these may be signs and symptoms of liver damage.