Pharmacokinetic and Phase I Evaluation of Carboplatin in Dogs

Abstract

Thirty dogs with spontaneously occurring malignant neoplasms were treated monthly with carboplatin (CBDCA) given as a 30-minute intravenous infusion in a dose escalation study. Twenty-eight dogs were considered evaluable for toxicity. The maximally tolerated dose of CBDCA was conceptually defined as that dose, determined by logistic regression analyses of toxicity data, resulting in a 50% incidence of moderate toxicity (MOD,) or a 5% incidence of severe toxicity (SEV,). Each designated maximally tolerated dose was calculated for the first course of treatment only and for the first and second courses of treatment combined to estimate cumulative drug toxicity. The MOD, and SEV, for the first treatment course were 340 and 278 mg/MZ, respectively. MOD, and SEV, values for the first plus second treatment courses were 327 and 231 mg/MZ, respectively. The nadir of neutrophil and platelet counts occurred approximately 14 days after treatment. The mean neutrophil and platelet values for all dogs experiencing myelosuppression during the first two treatment courses were 1541 /pL and 62,600/& respectively. Nonparametric pharmacokinetic analysis of plasma CBDCA values suggested that half-life (T,,2), area-under-the-curve and total body clearance (CL,) were not dose dependent. Volume of distribution (VD,) significantly increased with dose only between 100 and 150 mg/M2, not between 150 and 300 mg/M2. Dose-independent serum CBDCA pharmacokinetic disposition indicates that detailed investigation of tissue CBDCA distribution would be warranted and may identify novel dosing strategies that could improve the therapeutic index of CBDCA by minimizing toxicity. IN PEOPLE, cis-diammine-1,1 -cyclobutane dicarboxylate platinum (11) carboplatin* (CBDCA, JM-8) is a second generation platinum compound that differs from cisplatin (CDDP) in its pharmacological properties and pattern of toxicity without reduction in clinical efficacy.

Spray-dried poly(D,L-lactide) microspheres containing carboplatin for veterinary use: In vitro and in vivo studies

“…It is an analog of cisplatin, with a similar spectrum of activity but with a short half-life (about 3 hours in the dog), because it binds to the plasmatic proteins. 23 CP is less nephrotoxic with respect to cisplatin, but it can cause thrombocytopenia. 24 The incorporation of CP into PDLLA microspheres and then their direct intratumoral injection would achieve high and sustained drug concentrations selectively in the tumor, thus reducing the number of administrations.…”

Evaluation of carboplatin sustained‐release delivery system in dogs with cancer

“…1988) when injected intravenously, and this drug is undetectable 24 h after injection (Page et al . 1993). …”

“…These diseases include but are not limited to squamous cell carcinoma, pleural adenocarcinomas, nasal carcinomas, thyroid adenocarcinomas, osteogenic sarcomas, urinary transitional cell carcinomas and malignant melanomas (Page et al . 1993; Chun et al . 1997, 2007; Hahn et al .…”

The Pharmacokinetics and Pharmacodynamics of GW395058, a Peptide Agonist of the Thrombopoietin Receptor, in the Dog, a Large‐Animal Model of Chemotherapy‐Induced Thrombocytopenia

“…catheter on day 0 and day 28. This dose was selected, based on a previous dose-escalation study, to produce an approximate 80% drop from baseline platelet numbers [22]. GW395058 was administered at a dose of 1.31 mg/kg.…”

“…Parameters measured were platelet count, mean platelet volume, platelet distribution width, plateletcrit, total and differential white blood cell counts, reticulocyte count, red blood cell count, hemoglobin concentration, hematocrit, red blood cell indices (MCV, MCH, and MCHC), and red blood cell distribution width. Hematologic effects reflecting bone marrow toxicity were categorized using published toxicity grading scales for dogs similar to World Health Organization toxicity grades for humans [22]. Serum samples (1 ml) for clinical chemistry analysis were collected prior to each carboplatin dose to assess potential non-marrow toxicity.…”