Irinotecan dosage

Exatecan is a novel synthetic camptothecin derivative with a unique hexacyclic structure. It does not require metabolic activation, whereas irinotecan does. In vitro experiments in various cell lines have suggested that exatecan may be 6 and 28 times more active than SN-38 (7-ethyl-lO-hydroxycamptothecin, the active metabolite of irinotecan) and topotecan respectively. Furthermore, it has a 2-10 times higher therapeutic index than irinotecan and topotecan. In addition, exatecan may even be active in P-glycoprotein-mediated multidrug-resistant tumor cells. Its dose-limiting adverse effects are neutropenia and liver dysfunction. The recommended dosages of exatecan for phase II trials are 0.5 mg/m /day or 0.3 mg/ m /day as a 30-minute infusion on 5 consecutive days for minimally pretreated and heavily pretreated patients respectively (14,15). 

Raymond E, Boige V, Faivre S, Sanderink GJ, Rixe O, Vernillet L, Jacques C, Gatineau M, Ducreux M, Armand JP. Dosage adjustment and pharmacokinetic profile of irinotecan in cancer patients with hepatic dysfunction. J Clin Oncol 2002 20(21) 4303-12. 

Based on the results of these trials, irinotecan shonld be considered standard second-line therapy for patients who have failed prior treatment with fluorouracil-based regimens. Either dosage regimen (irinotecan 125 mg/m IV weekly for 4 weeks followed by a 2-week rest period or 300 to 350 mg/m IV every 3 weeks) is acceptable. For the every 3-week regimen, initial administration of irinotecan at the lower dose should be considered for patients who have received significant prior pelvic or abdominal irradiation. Protracted continnons-infusion fluorouracil could be considered for those individuals with disease that no longer responds to bolus IV fluorouracil plus leucovorin or irinotecan. 

Approved dosage schednles of irinotecan (Camptosar) in the United States inclnde 125 mg/m as a 90-minute infusion administered weekly for 4 ont of 6 weeks 350 mg/m given every 3 weeks 100 mg/m every week or 150 ing/m every other week. Irinotecan has sigifificant clinical activity... 

The UK manufacturer of aprepitant recommends caution when it is used with antineoplastics that are metabolised by CYP3A4, particularly irinotecan, because of the possibility of increased toxicity with this drug. They also mention that etoposide, vinoreibine, docetaxel, paclitaxel, ifosfamide, imatinib, vinblastine and vincristine, were given without dosage adjustment for potential interactions, but as this was not a formal interaction study they recommend caution. However, with intravenous docetaxel, it appears that no important changes in pharmacokinetics occur, and therefore dosage adjustments are unlikely to be needed for this drug,... 

A pharmacokinetic study was undertaken in 6 patients who were being treated with intravenous irinotecan 125 mg/m once weekly for 4 weeks, followed by a 2 week rest period. Four days before the second dose of irinotecan, a 14-day course of 200 mg milk thistle seed extract (containing silymarin 80%) three times daily was started. The pharmacokinetics of irinotecan and its metabolites did not differ between week 1 (no milk thistle), week 2 (4 days of milk thistle) or week 3 (12 days of milk thistle). No dosage alterations would therefore be expected to be needed if milk thistle (standardised with silymarin 80%) is given with irinotecan. 

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