Phase I and pharmacokinetic study of a new taxoid, RPR 109881A, given as a 1-hour intravenous infusion in patients with advanced solid tumors
Phase I and pharmacokinetic study of a new taxoid, RPR 109881A, given as a 1-hour intravenous infusion in patients with advanced solid tumors
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DOI：
10.1200/jco.2000.18.17.3164
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发表时间：
2000-09-01
影响因子：
45.3
通讯作者：
Kashimura, M
中科院分区：
文献类型：
--
作者：
Kurata, T;Shimada, Y;Kashimura, M
目的：RPR 109881 A是一种新的半合成紫杉烷类化合物，其作用机制与多西他赛相似。本I期研究的目的是表征最大耐受剂量（MTD），毒性特征，药代动力学特征，和抗肿瘤效果的这种agent.Patients和方法：19名符合条件的晚期实体瘤患者参加。RPR 109881 A以15 - 75 mg/m2的剂量每3周一次静脉输注1小时给药。药代动力学评价在第一个cycle.Results：中性粒细胞增多症（发热性中性粒细胞增多症）和疲劳是剂量限制性毒性，在60和75 mg/m2的剂量，似乎是剂量相关的。血小板减少症和贫血都不常见。非血液学毒性通常为轻度。药代动力学研究表明，RPR 109881 A的血浆分布为双相或三相，总血浆清除率较高，分布容积较大，终末半衰期较长。RPR 109881 A的浓度-时间曲线下面积（AUC）和峰浓度似乎随剂量增加而成比例增加，表明药代动力学呈线性。48小时内的尿排泄量较低，平均为给药剂量的0.8 ± 0.36%。中性粒细胞计数下降百分比与RPR 109881 A的AUC之间存在显著相关性。在18个可评估的患者中，两个部分和两个轻微的反应被记录。结论：RPR 109881 A被认为是一个耐受性良好，有前途的紫杉烷类药物。MTD为75 mg/m2，II期研究的推荐剂量为60 mg/m2，每3周一次，每次1小时输注。(C)2000年，美国临床肿瘤学会。
Purpase: RPR 109881A is a new semisynthetic taxoid compound that has a similar mechanism of action to docetaxel. The purpose of this phase I study was to characterize the maximum-tolerated dose (MTD), toxicity profile, pharmacokinetic profile, and antitumor effects of this agent.Patients and Methods: Nineteen eligible patients with advanced solid tumors were enrolled. RPR 109881A was administered as a 1-hour intravenous infusion every 3 weeks at doses ranging from 15 to 75 mg/m(2). Pharmacokinetic evaluation was performed at the first cycle.Results: Neutropenia (febrile neutrapenia) and fatigue were dose-limiting toxicities at doses of 60 and 75 mg/m2 and seemed to be dose-related. Both thrombocytapenia and anemia were infrequent. Nonhematologic toxicities were generally mild. Pharmacakinetic studies indicated that RPR 109881A plasma disposition was bi- or triphasic, with a high total plasma clearance, a large volume of distribution, and a long terminal half-life. The area under the concentration-time curve (AUC) and the peak concentration of RPR 109881A seemed to increase with increasing dose proportionally, suggesting linear pharmacokinetics. Urinary excretion over 48 hours was low, with a mean of 0.8 +/- 0.36% of the administered doze. A significant relationship existed between the percentage decrease of neutraphil counts and the AUC of RPR 109881A. Among 18 assessable patients, two partial and two minor responses were documented.Conclusion: RPR 109881A was found to be a well-tolerated and promising taxoid agent. The MTD was 75 mg/m(2), and the recommended dose for phase II study was 60 mg/m2 as a 1-hour infusion every 3 weeks. (C) 2000 by American Society of Clinical Oncology.