Phase I and pharmacologic study of topotecan in patients with impaired renal function |
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Authors: | S O'Reilly EK Rowinsky W Slichenmyer RC Donehower AA Forastiere DS Ettinger TL Chen S Sartorius LB Grochow |
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Affiliation: | Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-8934, USA. |
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Abstract: | PURPOSE: To determine the toxicities, pharmacokinetics, and recommended doses of the topoisomerase I inhibitor, topotecan, in patients with varying degrees of renal excretory dysfunction. PATIENTS AND METHODS: Fourteen patients with normal renal function [creatinine clearance (CrCl) > or = 60 mL/min] and 28 patients with varying degrees of renal dysfunction were treated with topotecan 0.4 to 2.0 mg/m2/d as a 30-minute infusion for 5 consecutive days every 3 weeks. Plasma and urine samples were obtained to determine the disposition of topotecan. RESULTS: In patients with mild renal dysfunction (CrCl = 40 to 59 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients receiving topotecan 1.0 mg/m2/d and in two of five patients receiving topotecan 1.5 mg/m2/d. In patients with moderate renal dysfunction (CrCl = 20 to 39 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients who received topotecan 0.5 mg/m2/d, and in two of four patients receiving topotecan 1.0 mg/m2/d; these events were more frequently observed in extensively pretreated patients. Pharmacokinetic analyses showed significant correlations between CrCl and the plasma clearance of both total topotecan [Spearman's correlation coefficient (r2) = 0.65, P = .00001] and topotecan lactone (r2 = 0.65, P = .00003). Mean systemic plasma clearance of total topotecan was significantly reduced in patients with mild (P = .04) and moderate (P = .00006) renal dysfunction. There was no evidence of changes in the pharmacodynamic relationship between topotecan exposure (AUC) and myelotoxicity. CONCLUSION: Dose adjustments are required in patients with moderate, but not mild, renal impairment. For patients with moderate renal dysfunction, the recommended starting dose of topotecan is 0.75 mg/m2/d for 5 days every 3 weeks. Moreover, extensively pretreated patients need further dose reductions. |
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