Phase I and pharmacokinetic study of Genexol-PM, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies
Phase I and pharmacokinetic study of Genexol-PM, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies
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DOI：
10.1158/1078-0432.ccr-03-0655
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发表时间：
2004-06-01
影响因子：
11.5
通讯作者：
Bang, YJ
中科院分区：
文献类型：
--
作者：
Kim, TY;Kim, DW;Bang, YJ
目的：开发一种替代紫杉醇制剂的基本原理是考虑到cremoophor el相关的副作用，一种新的紫杉醇给药系统可能会增强其治疗效果。Genexol-PM是一种聚合物胶束配方紫杉醇不含cremoophor EL。进行了一项I期研究，以确定Genexol-PM在晚期难治性恶性肿瘤患者中的最大耐受剂量、剂量限制性毒性和药代动力学特征。实验设计：21例患者入组研究。Genexol-PM在没有预先用药的情况下，每3周静脉注射3小时。Genexol-PM剂量从135 mg/m(2)增加到390 mg/m(2)。结果：所有患者的毒性和反应均可评价。未见急性超敏反应。神经病变和肌痛是最常见的毒性。在第1周期，1例患者分别在230和300 mg/m剂量下发生3级肌痛(2)。390mg /m(2)时，3例患者中有2例发生4级中性粒细胞减少症或3级多发性神经病。因此，确定最大耐受剂量为390 mg/m(2)。21例患者中有3例部分缓解（14%）。在3例应答者中，2例对既往紫杉烷治疗难治性。从时间0到无穷远，曲线下的紫杉醇面积和紫杉醇的峰值或最大浓度似乎随着剂量的增加而增加，除了230 mg/m(2)，这表明Genexol-PM具有线性药代动力学。结论：主要的剂量限制性毒性是神经病变、肌痛和中性粒细胞减少，II期研究的推荐剂量为300 mg/m(2)。Genexol-PM被认为在避免预用药和递送更高剂量的紫杉醇而没有额外毒性方面优于传统紫杉醇。
Purpose: The rationale for developing an alternative paclitaxel formulation concerns Cremophor EL-related side effects, and a novel paclitaxel delivery system might augment its therapeutic efficacy. Genexol-PM is a polymeric micelle formulated paclitaxel free of Cremophor EL. A phase I study was performed to determine the maximum tolerated dosage, dose-limiting toxicities, and the pharmacokinetic profile of Genexol-PM in patients with advanced, refractory malignancies.Experimental Design: Twenty-one patients were entered into the study. Genexol-PM was i.v. administered over 3 h every 3 weeks without premedication. The Genexol-PM dose was escalated from 135 mg/m(2) to 390 mg/m(2).Results: All of the patients were evaluable for toxicity and response. Acute hypersensitivity reactions were not observed. Neuropathy and myalgia were the most common toxicities. During cycle 1, grade 3 myalgia occurred in 1 patient at 230 and 300 mg/m(2), respectively. At 390 mg/m(2), 2 of 3 patients developed grade 4 neutropenia or grade 3 polyneuropathy. Therefore, the maximum tolerated dosage was determined to be 390 mg/m(2). There were 3 partial responses (14%) among the 21 patients. Of the 3 responders, 2 were refractory to prior taxane therapy. The paclitaxel area under the curve from time 0 to infinity and peak or maximum paclitaxel concentration seemed to increase with escalating dose, except at 230 mg/m(2), which suggests that Genexol-PM has linear pharmacokinetics.Conclusion: The main dose-limiting toxicities were neuropathy, myalgia, and neutropenia, and the recommended dosage for a phase II study is 300 mg/m(2). Genexol-PM is believed to be superior to conventional paclitaxel in terms of the obviation of premedication and the delivery of higher paclitaxel doses without additional toxicity.