Drug Interactions between alpelisib and ifosfamide

GENERALLY AVOID: Grapefruit and/or grapefruit juice may reduce the efficacy of ifosfamide, whose anticancer effect is dependent on its activation to the 4-hydroxyifosfamide metabolite via CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4 metabolism by certain compounds present in grapefruit. There are no data available about the effects of grapefruit on ifosfamide. However, in a small study, 8 patients with incurable malignancies received ifosfamide 3 g/m2 by infusion with the potent CYP450 3A4 inhibitor ketoconazole 200 mg orally twice daily for 4 days starting 1 day before the ifosfamide infusion. Ketoconazole decreased the clearance of ifosfamide by 11%, decreased systemic exposure (AUC) of the active metabolite 4-hydroxyifosfamide by 30%, and increased the AUC of the inactive but potentially neurotoxic metabolite 2-dechloroethylifosfamide by 23%, as compared to control. Because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

GENERALLY AVOID: Alcohol may potentiate the neurotoxic effects of ifosfamide. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills. In addition, ifosfamide therapy may cause gastrointestinal disorders and alcohol consumption may increase nausea and vomiting.

MANAGEMENT: Given the potential for reduced efficacy of ifosfamide and increased risk of neurotoxicity and nephrotoxicity it may be advisable for patients to avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with ifosfamide. In addition, patients receiving ifosfamide should be warned of the increased risk of neurotoxicity, nausea and vomiting when used in combination with alcohol. Patients should avoid or limit the consumption of alcohol during treatment with ifosfamide.

ADJUST DOSING INTERVAL: Food significantly enhances the oral absorption and bioavailability of alpelisib. When administered with a high-fat high-calorie meal (985 calories with 58.1 g of fat) or a low-fat low-calorie meal (334 calories with 8.7 g of fat) the AUC and Cmax of a single dose of alpelisib was increased by 73% and 84% and 77% and 145%, respectively. There were no clinically significant differences in alpelisib AUC between the two types of meals. In addition, food appears to have a more pronounced effect on the solubility of alpelisib than gastric pH. When coadministered with a single 300 mg dose of alpelisib, ranitidine decreased the absorption and overall exposure of alpelisib. Following administration of ranitidine with a low-fat low-calorie meal, the mean AUC and Cmax of alpelisib was decreased by 21% and 36%, respectively. Administration of ranitidine under fasting conditions reduced the mean AUC and Cmax of alpelisib by 30% and 51%, respectively.

MANAGEMENT: To ensure maximal oral absorption, alpelisib should be administered with a meal.