Objective—To determine the maximum tolerated dose and characterize the pharmacokinetic disposition of an orally administered combination of docetaxel and cyclosporin A (CSA) in dogs with tumors.
Animals—16 client-owned dogs with metastatic or advanced-stage refractory tumors.
Procedures—An open-label, dose-escalation, singledose, phase I study of docetaxel administered in combination with a fixed dose of CSA was conducted. Docetaxel (at doses of 1.5, 1.625, or 1.75 mg/kg) and CSA (5 mg/kg) were administered concurrently via gavage twice during a 3-week period. Plasma docetaxel concentrations were quantified by use of high-performance liquid chromatography, and pharmacokinetic disposition was characterized by use of noncompartmental analysis. Dogs' clinical signs and results of hematologic and biochemical analyses were monitored for evidence of toxicosis.
Results—No acute hypersensitivity reactions were observed after oral administration of docetaxel. Disposition of docetaxel was dose independent over the range evaluated, and pharmacokinetic variables were similar to those reported in previous studies involving healthy dogs, with the exception that values for clearance were significantly higher in the dogs reported here. The maximum tolerated dose of docetaxel was 1.625 mg/kg. Gastrointestinal signs of toxicosis were dose limiting.
Conclusions and Clinical Relevance—The absence of myelosuppression suggested that the docetaxelCSA combination may be administered more frequently than the schedule used. Further studies are warranted to evaluate combination treatment administered on a biweekly schedule in dogs with epithelial tumors.
Objective—To determine the maximally tolerated dose (MTD) and dose-limiting toxicosis (DLT) of ifosfamide in tumor-bearing cats.
Animals—38 cats with resected, recurrent, or metastatic sarcomas.
Procedure—The starting dosage of ifosfamide was 400 mg/m2 of body surface area, IV, and dosages were increased by 50 to 100 mg/m2 in cohorts of 3 cats. To protect against urotoxicosis, mesna was administered at a dosage equal to 20% of the calculated ifosfamide dosage. Diuresis with saline (0.9% NaCl) solution before and after administration of ifosfamide was used to minimize nephrotoxicosis. Samples for pharmacokinetic analysis were obtained after the MTD was reached.
Results—38 cats were entered into this phase I study and were administered a single dose of ifosfamide at various dosages. The MTD was 1,000 mg/m2, and neutropenia was the DLT. Seven of 8 episodes of neutropenia were on day 7 after treatment, and 1 cat developed severe neutropenia on day 5. Adverse effects on the gastrointestinal tract were generally mild and self-limiting, the most common of which was nausea during ifosfamide infusion. One cat had signs consistent with a drug-induced hypersensitivity reaction. There were no episodes of hemorrhagic cystitis or nephrotoxicosis. Correlations between pharmacokinetic variables and ifosfamide-associated toxicoses were not found. Preliminary evidence of antitumor activity was observed in 6 of 27 cats with measurable tumors.
Conclusions and Clinical Relevance—The dosage of ifosfamide recommended to treat tumor-bearing cats is 900 mg/m2 every 3 weeks. This dosage should be used in phase II clinical trials.
Objective—To characterize oral bioavailability and pharmacokinetic disposition of etoposide when the IV formulation was administered orally to dogs.
Animals—8 tumor-bearing dogs.
Procedures—An open-label, single-dose, 2-way crossover study was conducted. Dogs were randomly assigned to initially receive a single dose of etoposide (50 mg/m2) IV or PO. A second dose was administered via the alternate route 3 to 7 days later. Medications were administered before IV administration of etoposide to prevent hypersensitivity reactions. Oral administration of etoposide was prepared by reconstituting the parenteral formulation with 0.9% NaCl solution and further diluting the reconstituted mixture 1:1 with a sweetening agent. Plasma samples were obtained after both treatments. Etoposide concentrations were measured with a high-performance liquid chromatography assay, and plasma etoposide concentration–time profiles were analyzed by use of noncompartmental methods.
Results—4 dogs had hypersensitivity reactions during IV administration of etoposide. No adverse effects were detected after oral administration. Plasma etoposide concentrations were undetectable in 2 dogs after oral administration. Oral administration of etoposide resulted in significantly lower values for the maximum plasma concentration and the area under the plasma etoposide concentration-versus-time curve, compared with results for IV administration. Oral bioavailability of etoposide was low (median, 13.4%) and highly variable among dogs (range, 5.7% to 57.3%).
Conclusions and Clinical Relevance—Vehicle-related toxicosis can limit the IV administration of etoposide in dogs. The parenteral formulation of etoposide can be safely administered orally to dogs, but routine use was not supported because of low and variable oral bioavailability in this study.