9-氨基喜树碱胶体分散体制剂的I期和药理学研究，给药方式为每5周每周一次24小时持续输注，共四次。

Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation given as a 24-hour continuous infusion weekly times four every 5 weeks.

作者信息

Siu L L, Oza A M, Eisenhauer E A, Firby P S, Thiessen J J, Michael M, Wainman N, Manzo J, Feld R, Goldberg R A, Moore M J

机构信息

Department of Medicine, Princess Margaret Comprehensive Cancer Centre, Faculty of Pharmacy, University of Toronto, Ontario, Canada.

出版信息

J Clin Oncol. 1998 Mar;16(3):1122-30. doi: 10.1200/JCO.1998.16.3.1122.

DOI:10.1200/JCO.1998.16.3.1122

PMID:9508199

Abstract

PURPOSE

9-Aminocamptothecin (9-AC) is a water-insoluble camptothecin (CMP) derivative that inhibits normal topoisomerase I function. Schedule dependency was noted, with the greatest activity seen in the setting of greater than 24 hours exposure to lactone (L) concentrations > or = 10 nmol/L. In this phase I study, 9-AC was given by a continuous intravenous infusion over 24 hours once weekly times four every 5 weeks.

PATIENTS AND METHODS

Twenty patients, of whom 16 had fluorouracil-refractory colorectal cancer (CRC), entered the study. Dose levels were 0.7 mg/m2 (n = 4), 1.4 mg/m2 (n = 3), 1.9 mg/m2 (n = 6), and 1.65 mg/m2 (n = 7). Detailed pharmacokinetic (PK) measurements of 9-AC L and carboxylate (C) were performed on day 1 of cycles 1 and 2.

RESULTS

At 1.9 mg/m2, dose-limiting toxicity (DLT) was reached, with three of six patients having grade 4 neutropenia. At 1.65 mg/m2, one of seven patients had grade 4 neutropenia. Nonhematologic toxicity was modest, with diarrhea > or = grade 3 in two patients and lethargy > or = grade 3 in eight. PK/pharmacodynamic (PD) analyses showed marked interpatient variability. Steady-state concentrations (Css) of 9-AC L > or = 10 nmol/L (3.6 microg/L) were seen in five of seven patients at 1.65 mg/m2 and five of six patients at 1.9 mg/m2. Using the sigmoidal maximal effect (Emax) model, 9-AC L area under the concentration-time curve (AUC) and Css correlated with day 15 decrease in neutrophils (R2 = .47), but not platelets.

CONCLUSION

The recommended phase II dose of 9-AC colloidal dispersion (CD) given as a 24-hour continuous infusion weekly for 4 of every 5 weeks is 1.65 mg/m2.

摘要

目的

9-氨基喜树碱（9-AC）是一种水不溶性喜树碱（CMP）衍生物，可抑制正常拓扑异构酶I的功能。已观察到给药方案的依赖性，内酯（L）浓度≥10 nmol/L且暴露时间超过24小时时活性最高。在这项I期研究中，9-AC通过连续静脉输注24小时给药，每周一次，共四次，每5周重复一次。

患者与方法

20名患者进入本研究，其中16例患有氟尿嘧啶难治性结直肠癌（CRC）。剂量水平分别为0.7 mg/m²（n = 4）、1.4 mg/m²（n = 3）、1.9 mg/m²（n = 6）和1.65 mg/m²（n = 7）。在第1周期和第2周期的第1天对9-AC的L和羧酸盐（C）进行了详细的药代动力学（PK）测量。

结果

在1.9 mg/m²剂量时达到了剂量限制性毒性（DLT），6名患者中有3名出现4级中性粒细胞减少。在1.65 mg/m²剂量时，7名患者中有1名出现4级中性粒细胞减少。非血液学毒性较轻，2名患者出现≥3级腹泻，8名患者出现≥3级嗜睡症状。PK/药效学（PD）分析显示患者间存在显著差异。在1.65 mg/m²剂量组的7名患者中有5名、1.9 mg/m²剂量组的6名患者中有5名观察到9-AC L的稳态浓度（Css）≥10 nmol/L（3.6 μg/L）。使用S型最大效应（Emax）模型，9-AC L浓度-时间曲线下面积（AUC）和Css与第15天中性粒细胞减少相关（R² = 0.47），但与血小板无关。