Blaney S M, Balis F M, Cole D E, Craig C, Reid J M, Ames M M, Krailo M, Reaman G, Hammond D, Poplack D G
Walter Reed Army Medical Center, Washington, D.C. 20307.
Cancer Res. 1993 Mar 1;53(5):1032-6.
Topotecan, a water-soluble semisynthetic analogue of camptothecin, is the first topoisomerase I inhibitor to undergo evaluation in pediatric patients with refractory malignancies. A phase I and pharmacokinetic study was performed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities, the incidence and severity of other toxicities, and the pharmacokinetics of topotecan in children. Twenty-nine patients received 42 courses of i.v. topotecan administered as a 24-h continuous infusion every 21 days at doses ranging from 2.0 to 7.5 mg/m2. Dose-related hematological toxicity was the dose-limiting toxicity. Leukopenia, neutropenia, and thrombocytopenia occurred sporadically at the 3.0- to 5.5-mg/m2 dose levels, but at 7.5 mg/m2 4 of 5 patients experienced dose-limiting thrombocytopenia (grade 4) and 2 of 5 had dose-limiting neutropenia (grade 4). No other dose-limiting toxicities were observed. Nausea and vomiting were mild and occurred in < 20 and 10% of patients, respectively. Grade 2 hematuria occurred in one patient. No objective responses were observed. Pharmacokinetic studies revealed a linear relationship between the steady-state topotecan concentration and dose. The mean steady-state concentration at the MTD was 18.2 +/- 3.7 nmol/liter and the total body clearance was 28.3 +/- 6.5 liters/h/m2. Elimination was biexponential with a t1/2 alpha of 14.4 +/- 1.8 min and a t1/2 beta of 2.9 +/- 1.1 h. The recommended starting dose for phase II pediatric trials is 5.5 mg/m2. Although this dose exceeds the MTD identified in heavily pretreated adult patients receiving topotecan on the same schedule, it is less than the MTD for minimally pretreated adult patients. Therefore, dose escalation to 7.5 mg/m2 in phase II pediatric trials should be considered for patients who tolerate treatment well at the 5.5-mg/m2 dose.
拓扑替康是喜树碱的水溶性半合成类似物，是首个在难治性恶性肿瘤儿科患者中进行评估的拓扑异构酶I抑制剂。进行了一项I期药代动力学研究，以确定最大耐受剂量（MTD）和剂量限制性毒性、其他毒性的发生率和严重程度，以及拓扑替康在儿童中的药代动力学。29例患者接受了42个疗程的静脉注射拓扑替康，每21天进行一次24小时持续输注，剂量范围为2.0至7.5mg/m²。剂量相关的血液学毒性是剂量限制性毒性。白细胞减少、中性粒细胞减少和血小板减少在3.0至5.5mg/m²剂量水平时偶有发生，但在7.5mg/m²时，5例患者中有4例出现剂量限制性血小板减少（4级），5例中有2例出现剂量限制性中性粒细胞减少（4级）。未观察到其他剂量限制性毒性。恶心和呕吐较轻，分别发生在<20%和10%的患者中。1例患者出现2级血尿。未观察到客观缓解。药代动力学研究显示稳态拓扑替康浓度与剂量之间呈线性关系。MTD时的平均稳态浓度为18.2±3.7nmol/升，全身清除率为28.3±6.5升/小时/m²。消除呈双指数，t1/2α为14.4±1.8分钟，t1/2β为2.9±1.1小时。II期儿科试验的推荐起始剂量为5.5mg/m²。尽管该剂量超过了按相同方案接受拓扑替康治疗的重度预处理成年患者确定的MTD，但低于轻度预处理成年患者的MTD。因此，对于在5.5mg/m²剂量下耐受良好的患者，II期儿科试验中应考虑将剂量增至7.5mg/m²。
