Phase I and pharmacokinetic study of irinotecan administered as a low-dose, continuous intravenous infusion over 14 days in patients with malignant solid tumors
Phase I and pharmacokinetic study of irinotecan administered as a low-dose, continuous intravenous infusion over 14 days in patients with malignant solid tumors
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DOI：
10.1200/jco.1999.17.6.1897
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发表时间：
1999-06-01
影响因子：
45.3
通讯作者：
Huinink, WWT
中科院分区：
文献类型：
--
作者：
Herben, VMM;Schellens, JHM;Huinink, WWT
目的：评估伊立替康连续静脉输注 14 至 21 天的可行性。 患者和方法：对标准治疗难治的实体瘤患者通过流动输液泵接受伊立替康连续输注。起始剂量为 12.5 mg/m(2)/d，每 3 周持续 14 天。在确定 14 天输注计划的最大耐受剂量后，对方案进行了修改，将输注持续时间延长至 17 和 21 天。使用高效液相色谱和非房室模型测定伊立替康和SN-38及其葡萄糖醛酸苷的药代动力学。 结果：33名患者接受了85个以上疗程，在第一个剂量水平（12.5 mg/m(2)/d）时，5名患者中的3名出现累积3或4级腹泻和3或4级中性粒细胞减少症。在剂量为10 mg/m(2)/d时，给药14天导致6名患者中的2名出现4级腹泻，并发生1次4级呕吐，而给药17天时，6名患者观察到1次3级恶心和2次3或4级腹泻。由于累积性腹泻，将输注天数增加至21天是不可行的。血液学毒性很少见。平均代谢SN-38曲线下面积/伊立替康曲线下面积比率为16%+/-6%，而在涉及治疗剂量的短期输注计划后为3%至5%。在两名卵巢外癌和结直肠癌患者中观察到部分缓解。结论：推荐剂量为10 mg/m(2)/d，持续14天，每3周重复一次。伊立替康向 SN-38 的代谢增强可能部分解释了该方案的低推荐剂量。(C) 1999 年，美国临床肿瘤学会。
Purpose: To evaluate the feasibility of administering irinotecan as a continuous intravenous infusion for 14 to 21 days.Patients and Methods: patients with solid tumors refractory to standard therapy received continuous infusions of irinotecan by means of an ambulatory infusion pump. The starting dosage was 12.5 mg/m(2)/d for 14 days every 3 weeks. After identification of the maximum-tolerated dose for the 14-day infusion schedule, the protocol was amended to prolong the infusion duration to 17 and 21 days. pharmacokinetics of irinotecan and SN-38 and its glucuronide were determined using high-performance liquid chromatography and noncompartmental modeling.Results: Thirty-three patients received 85+ courses, At the first dose level (12.5 mg/m(2)/d), cumulative grade 3 or 4 diarrhea and grade 3 or 4 neutropenia occurred in three of five patients. At a dosage of 10 mg/m(2)/d, 14-day administration resulted in grade 4 diarrhea in two of six patients and one episode of grade 4 vomiting occurred, whereas with 17-day administration, one episode of grade 3 nausea and two episodes of grade 3 or 4 diarrhea were observed in six patients, Increasing the number of days of infusion to 21 days was not feasible because of cumulative diarrhea. Hematologic toxicity was rare. the mean metabolic SN-38 area under the curve/irinotecan area under the curve ratio wets 16% +/- 6% compared with 3% to 5% after short infusion schedules involving therapeutic dosages. partial responses were observed in two patients with extraovarian and colorectal cancer.Conclusion: the recommended dosage is 10 mg/ m(2)/d for 14 days, repeated every 3 weeks. Enhanced metabolism of irinotecan to SN-38 may explain in part the low recommended dose for this schedule.(C) 1999 by American Society of Clinical Oncology.