Phase I and pharmacologic study of topotecan in patients with impaired renal function

S. O'Reilly, E. K. Rowinsky, W. Slichenmyer, Ross C Donehower, Arlene A. Forastiere, David S Ettinger, T. L. Chen, S. Sartorius, L. B. Grochow

Research output: Contribution to journalArticle

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) ≤ 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 (r(s)) = 0.65, P = .00001] and topotecan lactone (r(s) = 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.

Original languageEnglish (US)
Pages (from-to)3062-3073
Number of pages12
JournalJournal of Clinical Oncology
Volume14
Issue number12
StatePublished - 1996

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Topotecan
Kidney
Creatinine
Pharmacokinetics
Topoisomerase I Inhibitors
Lactones

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I and pharmacologic study of topotecan in patients with impaired renal function. / O'Reilly, S.; Rowinsky, E. K.; Slichenmyer, W.; Donehower, Ross C; Forastiere, Arlene A.; Ettinger, David S; Chen, T. L.; Sartorius, S.; Grochow, L. B.

In: Journal of Clinical Oncology, Vol. 14, No. 12, 1996, p. 3062-3073.

Research output: Contribution to journalArticle

O'Reilly, S, Rowinsky, EK, Slichenmyer, W, Donehower, RC, Forastiere, AA, Ettinger, DS, Chen, TL, Sartorius, S & Grochow, LB 1996, 'Phase I and pharmacologic study of topotecan in patients with impaired renal function', Journal of Clinical Oncology, vol. 14, no. 12, pp. 3062-3073.
O'Reilly, S. ; Rowinsky, E. K. ; Slichenmyer, W. ; Donehower, Ross C ; Forastiere, Arlene A. ; Ettinger, David S ; Chen, T. L. ; Sartorius, S. ; Grochow, L. B. / Phase I and pharmacologic study of topotecan in patients with impaired renal function. In: Journal of Clinical Oncology. 1996 ; Vol. 14, No. 12. pp. 3062-3073.
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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) ≤ 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 (r(s)) = 0.65, P = .00001] and topotecan lactone (r(s) = 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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T1 - Phase I and pharmacologic study of topotecan in patients with impaired renal function

AU - O'Reilly, S.

AU - Rowinsky, E. K.

AU - Slichenmyer, W.

AU - Donehower, Ross C

AU - Forastiere, Arlene A.

AU - Ettinger, David S

AU - Chen, T. L.

AU - Sartorius, S.

AU - Grochow, L. B.

PY - 1996

Y1 - 1996

N2 - 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) ≤ 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 (r(s)) = 0.65, P = .00001] and topotecan lactone (r(s) = 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.

AB - 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) ≤ 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 (r(s)) = 0.65, P = .00001] and topotecan lactone (r(s) = 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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