Maier-Lenz H, Hauns B, Haering B, Koetting J, Mross K, Unger C, Bauknecht T, du Bois A, Meerpohl H G, Hollaender N, Diergarten K
Department of Clinical Pharmacology, Tumor Biology Center, Freiburg, Germany.
Semin Oncol. 1997 Dec;24(6 Suppl 19):S19-16-S19-19.
Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of the most important new drugs used in the treatment of solid tumors. Use of paclitaxel, however, is associated with some toxicity. The main adverse side effects include myelotoxicity, neurotoxicity, hypersensitivity reactions, and asthenia. Toxicity seems to be schedule dependent. Currently, paclitaxel is routinely administered via 3- or 24-hour infusions. This study was performed to evaluate the toxicity and pharmacokinetics of a 1-hour infusion. Thirty-four patients with incurable solid tumors were included. Dose levels were escalated from 150 to 250 mg/m2. Thirty-four patients received a total of 105 courses of paclitaxel. The dose-limiting toxicity was World Health Organization grade 3 neuropathy at a dose of 250 mg/m2 in two of three patients. Two patients were not evaluable for dose-limiting toxicity because treatment was stopped after fewer than three courses due to disease progression. Neither had experienced a dose-limiting toxicity. Other toxicities were World Health Organization grade 1/2 neutropenia, asthenia, myalgia, arthralgia, and grade 1 hypersensitivity. Twenty-one patients were evaluable for preliminary anticancer efficacy. A partial response was observed in five patients (24%), stable disease in three (14%), and progressive disease in 13 (62%). The maximum tolerated dose was established at 250 mg/m2. A dose of 225 mg/m2 is recommended for further phase II trials. There was considerable interindividual and some intraindividual variability in pharmacokinetic parameters. Paclitaxel pharmacokinetics were linear up to 225 mg/m2, while a slightly overproportional increase in the peak plasma concentration and the area under the concentration-time curve was observed at 250 mg/m2, suggesting that paclitaxel's pharmacokinetic characteristics may be nonlinear at higher doses.
紫杉醇（泰素；百时美施贵宝公司，新泽西州普林斯顿）是用于治疗实体瘤的最重要的新药之一。然而，使用紫杉醇会产生一些毒性。主要的不良副作用包括骨髓毒性、神经毒性、过敏反应和乏力。毒性似乎与给药方案有关。目前，紫杉醇通常通过3小时或24小时静脉输注给药。本研究旨在评估1小时静脉输注的毒性和药代动力学。纳入了34例无法治愈的实体瘤患者。剂量水平从150mg/m²逐步递增至250mg/m²。34例患者共接受了105个疗程的紫杉醇治疗。剂量限制性毒性为3例患者中有2例在剂量为250mg/m²时出现世界卫生组织3级神经病变。2例患者因疾病进展在少于3个疗程后停止治疗，无法评估剂量限制性毒性。这2例患者均未出现剂量限制性毒性。其他毒性包括世界卫生组织1/2级中性粒细胞减少、乏力、肌痛、关节痛和1级过敏反应。21例患者可评估初步抗癌疗效。5例患者（24%）观察到部分缓解，3例（14%）病情稳定，13例（62%）病情进展。最大耐受剂量确定为250mg/m²。建议在进一步的II期试验中使用225mg/m²的剂量。药代动力学参数存在相当大的个体间差异和一些个体内差异。紫杉醇药代动力学在高达225mg/m²时呈线性，而在250mg/m²时观察到血浆峰浓度和浓度-时间曲线下面积略有超比例增加，表明紫杉醇在较高剂量下的药代动力学特征可能是非线性的。
