Topotecan dosage

A 5-year-old child with medulloblastoma received a course of topotecan, firstly with phenytoin and then without. Phenytoin increased the total topotecan clearance by 47%. This suggests that an increased topotecan dosage may possibly be needed in the presence of phenytoin in other patients. For a similar effect of antiepileptics on related topoisomerase inhibitors, see Trinotecan + Antiepileptics , p.638 and 9-Aminocamptothecin + Antiepileptics , p.610. 

The camptothecins are natural products that are derived from the Camptotheca acuminata tree, and they inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands. Inhibition of the enzyme results in DNA damage. Topotecan is indicated in the treatment of patients with advanced ovarian cancer who have failed platinum-based chemotherapy and is also approved as second-line therapy of small cell lung cancer. The main route of elimination is renal excretion, and for this reason caution must be exercised in patients with abnormal renal function, with dosage reduction being required. 

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). 

Topotecan has been approved for the treatment of advanced pretreated ovarian and small-ceU lung cancer in several countries. After intravenous administration of conventional dosages (for example 1.5 mg/m /day for 5 consecutive days) its half-life is 2-4 hours. Prolonged infusion for 3, 5, or 21 days increases drug exposure without affecting the disposition of topotecan (29). 

Myelosuppression, neutropenia, and to a lesser extent thrombocytopenia, are dose-limiting toxic effects of topotecan. Reversible non-cumulative neutropenia usually occurs at between days 8 and 15 after an intravenous dosage of 1.5 mg/m on five consecutive days. The nadir of the neutrophil count occurs on day 11, with recovery on day 21. Neutropenia, with cell counts less than 1.5 x lO /l (grade 2) and 0.5 x 10 /1 (grade 4), is observed in 70-97% of patients. In addition, 4-33% of patients treated with conventional dosages of topotecan develop neutropenic fever (97-99). 

Topotecan elimination is biphasic, with a terminal half-life of 2.0 to 3.5 hours. Lactone hydrolysis is rapid, and binding to serum proteins is limited to between 25 and 40%. CYP3A4-mediated N-dealkylation to mono-and didealkylated metabolites occurs to a limited extent, and the 0-glucuronides that form at multiple points along the metabolic path are excreted via the kidney (Fig. 42.41). Extensive renal clearance demands dosage adjustment in patients with kidney disease. 

Up to the end of 1995, many results of phase II clinical studies on CPT-11 and topotecan administered intravenously have been presented and summarized [183, 184, 187,188]. In phase II studies of CPT-11 against solid tumours, the most popular dosage schedules were 100 mg/m /day once weekly or 150 mg/m /day once every 2 weeks in Japan, 125 mg/m /day once weekly in U.S.A., and 350 mg/m /day once every 3 weeks in Europe. On the other hand, topotecan was infused for 30 min at doses of 1.25-2.0 (dominantly 1.5) mg/m /day once for 5 consecutive days every 3 weeks. Usually, the dose-limiting toxicity of CPT-11 is myelosuppression (mainly neutropenia)... 

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