O'Dwyer P J, LaCreta F P, Haas N B, Halbherr T, Frucht H, Goosenberg E, Yao K S
Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
Cancer Chemother Pharmacol. 1994;34 Suppl:S46-52. doi: 10.1007/BF00684863.
The topoisomerase I inhibitor topotecan is a potent water-soluble camptothecin derivative with activity in a wide variety of preclinical models. Topotecan exhibits schedule dependency in vivo, with the greatest activity being observed on repeated dose schedules. On the basis of the initial clinical studies that showed a short plasma half-life, we attempted to prolong drug exposure by giving topotecan as a 24-h infusion weekly. In a phase I trial, we treated 32 patients at doses ranging from 1.0 to 2.0 mg/m2. The patient population had not been heavily pretreated with chemotherapy and was of good performance status. The incidence of neutropenia, which was dose-limiting, increased sharply with relatively small increments in dose. Doses greater than 1.5 mg/m2 were associated with nadirs that developed after one to three weekly treatments. A patient with metastatic colorectal cancer had a prolonged partial response. The plasma pharmacokinetics of topotecan (lactone and open forms) was characterized in 21 patients. Mean plasma steady-state drug levels were proportional to the dose and were within the range required to exert cytotoxicity in preclinical models. Plasma elimination curves were fit to a one-compartment model, in which the harmonic mean half-life of topotecan was 3.5 h. The ratio of the lactone to the total drug concentrations was constant throughout, which suggests that for this schedule the total drug concentration may be used as a measure of active lactone exposure. This conclusion is supported by the pharmacodynamic analysis, which revealed a positive correlation of both lactone and total drug steady-state concentrations with bone marrow toxicity. The further investigation of this and other infusional schedules in phase II trials will be conducted. The steady-state concentrations of total drug will be measured in several of these trials to establish its potential role in adaptive dosing using this schedule. Such a strategy is justified by the interpatient variability in toxicity and the steep dose-response curve observed in this study. Preliminary evidence of interpatient variability in the mRNA expression of topoisomerase I in the peripheral mononuclear cells and colon mucosa is presented. Trials are under way using biological endpoints for further selection of patients in whom the use of topoisomerase inhibitors may be therapeutically beneficial.
拓扑异构酶I抑制剂拓扑替康是一种有效的水溶性喜树碱衍生物，在多种临床前模型中均有活性。拓扑替康在体内表现出给药方案依赖性，重复给药方案时活性最高。基于最初显示血浆半衰期较短的临床研究，我们尝试通过每周24小时持续输注拓扑替康来延长药物暴露时间。在一项I期试验中，我们以1.0至2.0mg/m²的剂量治疗了32例患者。患者群体未接受过大量化疗预处理，且身体状况良好。作为剂量限制毒性的中性粒细胞减少症的发生率，随着剂量相对较小的增加而急剧上升。剂量大于1.5mg/m²与一至三次每周治疗后出现的最低点相关。一名转移性结直肠癌患者出现了延长的部分缓解。对21例患者的拓扑替康（内酯和开环形式）血浆药代动力学进行了表征。平均血浆稳态药物水平与剂量成正比，且在临床前模型中发挥细胞毒性所需的范围内。血浆消除曲线符合一室模型，其中拓扑替康的调和平均半衰期为3.5小时。内酯与总药物浓度的比值始终恒定，这表明对于该给药方案，总药物浓度可作为活性内酯暴露的一种度量。药效学分析支持了这一结论，该分析揭示内酯和总药物稳态浓度与骨髓毒性均呈正相关。将在II期试验中对该给药方案及其他持续输注方案进行进一步研究。将在其中一些试验中测量总药物的稳态浓度，以确定其在使用该给药方案进行适应性给药中的潜在作用。这种策略因本研究中观察到的患者间毒性变异性和陡峭的剂量反应曲线而合理。给出了外周单核细胞和结肠黏膜中拓扑异构酶I的mRNA表达存在患者间变异性的初步证据。正在进行使用生物学终点的试验，以进一步筛选可能从使用拓扑异构酶抑制剂中获益的患者。
