Drug Interactions between irinotecan and Phenytoin Sodium, Prompt

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of irinotecan and its pharmacologically active metabolite, SN-38. Irinotecan is partially metabolized by CYP450 3A4 to inactive substances, and induction of this process results in less of the drug available for conversion to SN-38 via hepatic carboxylesterases. Available data also suggest induction of other enzymatic pathways (e.g., UGT1A1; carboxylesterases) and drug transporters (e.g., multispecific organic anion transporter, or MRP2; mitoxantrone-resistance half transporter protein, or MXR) that may be involved in the clearance of irinotecan and/or SN-38, although the extent to which they contribute to the interaction is unknown. In a study of patients with malignant glioma, irinotecan clearance was 61% greater in the group receiving enzyme-inducing anticonvulsants (n=34) than in the group receiving other anticonvulsants (n=22). In a study of pediatric high-grade glioma patients, a 1.5-fold increase in the median clearance of irinotecan and a 20-fold decrease in the median systemic exposure to SN-38 were observed in patients receiving enzyme-inducing anticonvulsants compared to those not receiving the anticonvulsants. Patients receiving enzyme-inducing anticonvulsants in these studies also experienced milder toxicities or tolerated higher dosages of irinotecan. In a phase II clinical trial, patients receiving irinotecan for malignant glioma had an unusually low incidence of toxicity, and AUCs of irinotecan and SN-38 were 40% and 25%, respectively, of those determined previously in patients with metastatic colorectal cancer. A pharmacokinetic interaction was suspected, as more than 90% of the glioma patients received concomitant enzyme-inducing anticonvulsants and/or dexamethasone, while the colorectal cancer patients did not. In a pediatric case study, irinotecan pharmacokinetics were determined in a 15-year-old boy on day 1 of two treatment cycles (50 mg/m2 daily for 5 days every 21 days)--one before and one after the addition of phenytoin. Irinotecan clearance increased by 168% and the AUC of irinotecan and SN-38 decreased by 63% and 60%, respectively, in the presence of phenytoin. Similarly, in a 14-year-old girl receiving irinotecan daily for 5 days on two consecutive weeks every 21 days for two cycles, pharmacokinetic studies on day 8 of each cycle showed that irinotecan clearance decreased by 42% and the AUC of irinotecan and SN-38 increased by 76% and 138%, respectively, following discontinuation of phenytoin just prior to cycle 2.

MANAGEMENT: Concomitant use of irinotecan with potent CYP450 3A4 inducers should generally be avoided. Consideration should be given to substituting nonenzyme-inducing agents at least one to two weeks prior to initiation of irinotecan therapy whenever possible.

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