Drug Interactions between ifosfamide and paclitaxel protein-bound

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.

MONITOR: Coadministration with inhibitors of CYP450 3A4, such as grapefruit juice, may increase the plasma concentrations of paclitaxel, which is a substrate of the isoenzyme. Current data suggest that consumption of large quantities of grapefruit juice inhibit both intestinal and hepatic CYP450 3A4 due to certain compounds present in grapefruit. Specific data for paclitaxel are lacking; however, in a case report of a 52-year-old woman with esophageal squamous cell carcinoma receiving a twice weekly chemotherapy regimen including intravenous docetaxel (40 mg/m2) reported that docetaxel systemic exposure (AUC) increased by 65% compared with the AUC target of 1.96 mg*h/L and clearance decreased by 63%, with a 71% reduction in the patient's neutrophil count. In the absence of other CYP450 3A4 inhibitors, these effects were attributed to daily consumption of 250 mL of grapefruit juice, which the patient had been consuming for at least 3 months. Two weeks after the patient ceased the grapefruit juice, the docetaxel AUC was closer to the target value and the neutrophil count reduction was less than 35%. In addition, in a pharmacokinetic study consisting of 7 cancer patients, mean dose-normalized docetaxel AUC increased by 2.2-fold and clearance decreased by 49% when intravenous docetaxel was given at a reduced dosage of 10 mg/m2 in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally once daily for 3 days) compared to docetaxel administered alone at 100 mg/m2.

MANAGEMENT: Caution is recommended if paclitaxel is to be used in combination with grapefruit and grapefruit juice. Patients should be closely monitored for the development of paclitaxel toxicity, including diarrhea, mucositis, myelosuppression, and peripheral neuropathy and dose adjustment considered per local treatment protocols.