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Effect of glomerular filtration rate on clearance and myelotoxicity of carboplatin in cats with tumors

Dennis B. BaileyDepartment of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

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Kenneth M. RassnickDepartment of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

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Hollis N. ErbDepartment of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

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Nathan L. DykesDepartment of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

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P. Jack HoopesDepartment of Surgery, College of Medicine, Dartmouth College, Hanover, NH 03755.

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Rodney L. PageDepartment of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

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Abstract

Objective—To characterize the pharmacokinetic disposition of carboplatin and determine whether glomerular filtration rate (GFR) could be used to predict carboplatin clearance and myelotoxic effects in cats with tumors.

Animals—10 cats with tumors.

Procedure—Glomerular filtration rate was assessed in each cat by monitoring plasma clearance of technetium Tc 99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA). Each cat received carboplatin (200 mg/m2 of body surface area) administered as an IV bolus. Plasma platinum concentrations were measured via atomic absorption spectrophotometry, and pharmacokinetic analysis was performed. A CBC was performed weekly for each cat, and the correlation between the area under the concentration-versus-time curve (AUC) and the severity of myelosuppression was calculated. Least squares regression analysis was performed to determine whether GFR could be used to predict plasma platinum clearance (ClPt).

Results—For all cats, AUC measurements ranged from 0.99 to 4.30 min·mg·mL–1. Neutrophil concentration nadirs were detected 1 to 3 weeks after treatment and ranged from 200 to 8,000 cells/µL. The absolute neutrophil concentration at the nadir was inversely correlated with AUC. The ClPt was predicted by use of GFR measurements (ClPt = 2.60 × GFR). A carboplatin dose prescription model was derived involving AUC, estimated ClPt, and body weight in kilograms (BWkg), in which dose = AUC × 2.60(GFR) × BWkg.

Conclusions and Clinical Relevance—In cats, an individualized prescription strategy for carboplatin administration based on a targeted AUC and determination of GFR might more uniformly predict myelosuppression than that predicted by conventional dosing based on body surface area. (Am J Vet Res 2004;65:1502–1507)

Abstract

Objective—To characterize the pharmacokinetic disposition of carboplatin and determine whether glomerular filtration rate (GFR) could be used to predict carboplatin clearance and myelotoxic effects in cats with tumors.

Animals—10 cats with tumors.

Procedure—Glomerular filtration rate was assessed in each cat by monitoring plasma clearance of technetium Tc 99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA). Each cat received carboplatin (200 mg/m2 of body surface area) administered as an IV bolus. Plasma platinum concentrations were measured via atomic absorption spectrophotometry, and pharmacokinetic analysis was performed. A CBC was performed weekly for each cat, and the correlation between the area under the concentration-versus-time curve (AUC) and the severity of myelosuppression was calculated. Least squares regression analysis was performed to determine whether GFR could be used to predict plasma platinum clearance (ClPt).

Results—For all cats, AUC measurements ranged from 0.99 to 4.30 min·mg·mL–1. Neutrophil concentration nadirs were detected 1 to 3 weeks after treatment and ranged from 200 to 8,000 cells/µL. The absolute neutrophil concentration at the nadir was inversely correlated with AUC. The ClPt was predicted by use of GFR measurements (ClPt = 2.60 × GFR). A carboplatin dose prescription model was derived involving AUC, estimated ClPt, and body weight in kilograms (BWkg), in which dose = AUC × 2.60(GFR) × BWkg.

Conclusions and Clinical Relevance—In cats, an individualized prescription strategy for carboplatin administration based on a targeted AUC and determination of GFR might more uniformly predict myelosuppression than that predicted by conventional dosing based on body surface area. (Am J Vet Res 2004;65:1502–1507)