Irinotecan

Irinotecan (Camptosar) is a topoisomerase-I inhibitor that forms a complex with the covalently bound DNA topoisomerase I enzyme and interferes with the DNA breakage-resealing process.33, 4 Binding permits uncoiling of the double-stranded DNA, but it prevents subsequent resealing of the DNA, resulting in double-stranded DNA breaks. Irinotecan is a prodrug that is converted by carboxlyesterases to its active form SN-38. Irinotecan is indicated for the first-line treatment of metastatic colorectal cancer in combination with 5-fluorouracil and leucovorin or as a single agent in patients who fail first-line therapies. Irinotecan is not recommended as part of the adjuvant treatment of colorectal cancer at this time.

The major toxicity of irinotecan is diarrhea, which can occur both early and late in therapy.41,44 The early diarrhea is a cholinergic reaction that occurs in the first 24 hours (often during the infusion) in up to 10% of patients and responds to atropine 0.25 to 1 mg IV. The late diarrhea seen in a larger percent of patients occurs 7 to 14 days after the irinotecan infusion. Health care practitioners have to be diligent in counseling patients on this adverse reaction and counseling them on the proper use of antidiarrheals. At the first change in bowel habits, an intensive loperamide regimen should be started by patients (4 mg initially, followed by 2 mg every 2 hours until diarrhea-free for 12 hours). If diarrhea does not stop, or worsens, patients should be instructed to call their health care provider immediately. Late-onset diarrhea may require hospitalization or discontinuation of therapy, and fatalities have been reported. Additional toxicities with irinotecan include leukopenia (including neutropenic fever) and moderate nausea and vomiting. Toxicities of irinotecan appear to be greater when the drug is given weekly when compared to other administration schedules.

Similar to 5-fluorouracil, there is a pharmacogenomic abnormality associated with irinotecan toxicity. UDP-glucuronosyltransferase (UGT1A1) is an enzyme that is responsible for the glucuronidation of SN-38 to inactive metabolites, and reduced or deficient levels of this enzyme correlate with irinotecan-induced diarrhea and neut-ropenia.41,44,48 Recently, the FDA approved a blood test that detects variations in this gene. This test may assist health care providers in predicting which patients may develop severe toxicities from "normal" doses of irinotecan and can be ordered prior to patients receiving irinotecan.41 The package insert recommends dose reductions of one levels in patients who are UGT1A1 homozygous variants. Irinotecan is administered as an IV bolus over 60 to 90 minutes in a variety of dosing schedules.

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