McEntee Margaret C, Rassnick Kenneth M, Lewis Lionel D, Zgola Marsha M, Beaulieu Bernard B, Balkman Cheryl E, Page Rodney L
Section of Oncology, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Am J Vet Res. 2006 Jun;67(6):1057-62. doi: 10.2460/ajvr.67.6.1057.
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.
16 client-owned dogs with metastatic or advanced-stage refractory tumors.
An open-label, dose-escalation, single-dose, 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.
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.
The absence of myelosuppression suggested that the docetaxel-CSA 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.
确定多西他赛与环孢素A（CSA）口服联合用药在患肿瘤犬中的最大耐受剂量，并描述其药代动力学特征。
16只客户拥有的患有转移性或晚期难治性肿瘤的犬。
进行了一项开放标签、剂量递增、单剂量的多西他赛与固定剂量CSA联合用药的I期研究。多西他赛（剂量为1.5、1.625或1.75mg/kg）和CSA（5mg/kg）在3周内通过灌胃同时给药两次。使用高效液相色谱法定量血浆多西他赛浓度，并使用非房室分析法描述药代动力学特征。监测犬的临床体征以及血液学和生化分析结果，以寻找中毒证据。
口服多西他赛后未观察到急性过敏反应。在所评估的剂量范围内，多西他赛的处置与剂量无关，药代动力学变量与先前涉及健康犬的研究报告相似，但此处报告的犬的清除率值明显更高。多西他赛的最大耐受剂量为1.625mg/kg。中毒的胃肠道体征是剂量限制性的。
未出现骨髓抑制表明多西他赛与CSA联合用药的给药频率可能高于所用方案。有必要进一步研究评估每两周给药方案对患有上皮性肿瘤的犬进行联合治疗的效果。
