Phase I evaluation of carboplatin by use of a dosing strategy based on a targeted area under the platinum concentration-versus-time curve and individual glomerular filtration rate in cats with tumors.
OBJECTIVE
To determine whether a carboplatin dose calculation that is based on a targeted area under the concentration-versus-time curve (AUC(Target)) and individual glomerular filtration rate (GFR) accurately predicts carboplatin-associated myelotoxicoses in tumor-bearing cats, and to determine the maximum tolerated AUC(Target).


METHODS
32 cats with tumors.


METHODS
In each cat, plasma clearance of technetium Tc 99m-labeled diethylenetriaminepentaacetic acid was measured to assess GFR. Carboplatin was administered IV. The dose was calculated by use of an equation as follows: Dose = AUC(Target) x 2.6 x GFR x body weight. Initial AUC(Target) was 2.0 min.mg.mL(-1) and was increased in increments of 0.50 min.mg.mL(-1) in cohorts of 3 cats. To assess myelotoxic effects, CBCs were performed weekly for > or = 4 weeks. Following identification of the maximum tolerated AUC(Target), additional cats were treated at that AUC(Target) and plasma platinum concentrations were measured in 6 cats.


RESULTS
The AUC(Target) values ranged from 2.0 to 3.0 min.mg.mL(-1). Neutropenia was the dose-limiting toxicosis, and the maximum tolerated AUC(Target) was 2.75 min.mg.mL(-1). Nineteen cats received this dose of carboplatin; 13 became neutropenic, but only 1 developed severe neutropenia (< 500 neutrophils/microL), and none had neutropenia-associated clinical signs. In the cats that had plasma platinum concentration determined, the difference between AUC(Target) and the measured value ranged from -0.23 to 0.31 min.mg.mL(-1) (median, 0.20 min.mg.mL(-1)).


CONCLUSIONS
In cats, carboplatin-associated myelotoxicoses were accurately and uniformly predicted by use of the proposed dosing strategy. The maximum tolerated AUC(Target) for a single dose of carboplatin was 2.75 min.mg.mL(-1).
Bailey
Dennis B
DB
Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Rassnick
Kenneth M
KM
Dykes
Nathan L
NL
Pendyala
Lakshmi
L
D000180:Acrylic Resins; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D002371:Cat Diseases / Q000188:drug therapy*; D002415:Cats; D004305:Dose-Response Relationship, Drug; D005260:Female; D005919:Glomerular Filtration Rate; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000662:veterinary*; D011145:Polyvinyls / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*
D000180:Acrylic Resins; D000970:Antineoplastic Agents; D011145:Polyvinyls; C006912:carboxypolymethylene