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Phase I and pharmacologic study of topotecan in patients with impaired renal function
S O'Reilly1, E K Rowinsky, W Slichenmyer
1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-8934, USA.
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.
Insights
Topotecan dosing requires adjustment in moderate renal impairment to avoid toxicity. A starting dose of 0.75 mg/m2/d is recommended for patients with moderate renal dysfunction.
Area of Science:
- Pharmacology
- Oncology
- Nephrology
Background:
- Topotecan is a topoisomerase I inhibitor used in cancer treatment.
- Renal function significantly impacts drug clearance and toxicity.
- Understanding topotecan pharmacokinetics in renal dysfunction is crucial for safe dosing.
Purpose of the Study:
- To evaluate toxicities, pharmacokinetics, and optimal topotecan doses in patients with varying renal impairment.
- To establish safe and effective dosing strategies for topotecan in patients with compromised kidney function.
Main Methods:
- A cohort of 14 patients with normal renal function and 28 with renal dysfunction received topotecan (0.4-2.0 mg/m2/d).
- Plasma and urine samples were collected to analyze topotecan disposition.
- Creatinine clearance (CrCl) was used to categorize renal function (mild: 40-59 mL/min; moderate: 20-39 mL/min).
Main Results:
- Dose-limiting hematologic toxicity was observed in patients with mild and moderate renal dysfunction, particularly in extensively pretreated individuals.
- Significant correlations were found between CrCl and plasma clearance of total topotecan and topotecan lactone.
- Systemic clearance of topotecan was reduced in patients with mild and moderate renal dysfunction, with no change in the exposure-myelotoxicity relationship.
Conclusions:
- Dose adjustments for topotecan are necessary for patients with moderate renal impairment.
- A recommended starting dose of 0.75 mg/m2/d for 5 days every 3 weeks is proposed for moderate renal dysfunction.
- Extensively pretreated patients may require further dose reductions to mitigate toxicity.