Prolonged infusion of gemcitabine: Clinical and pharmacodynamic studies during a phase I trial in relapsed acute myelogenous leukemia
Prolonged infusion of gemcitabine: Clinical and pharmacodynamic studies during a phase I trial in relapsed acute myelogenous leukemia
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DOI：
10.1200/jco.20.3.665
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发表时间：
2002-02-01
影响因子：
45.3
通讯作者：
Estey, EH
中科院分区：
文献类型：
--
作者：
Gandhi, V;Plunkett, W;Estey, EH
目的：确定吉西他滨固定剂量率10mg /m(2)/min输注的最大耐受时间，分析吉西他滨治疗期间白血病母细胞的药效学作用。患者和方法：该研究是在一项I期试验中进行的，通过增加吉西他滨输注的持续时间，固定剂量率为10mg /m(2) /min。复发或难治性急性髓性白血病（AML）患者接受吉西他滨治疗的时间为8.0 （n = 3）、10.0 （n = 3）、12.5 （n = 8）、15.5 （n = 3）或18.0小时（n = 2）。在循环AML细胞中进行了药代动力学和药效学研究。结果：吉西他滨以固定闭合速率输注长达18小时。4例患者在较长的输注时间内出现3级毒性。一名患者部分缓解；另外两组细胞减少，同时中性粒细胞增加。在8例患者中，即使在开始输注后1小时，也可以在AML细胞中检测到三磷酸吉西他滨。注射结束时浓度为130 ~ 900 μ mol/L。与此一致的是，DNA合成迅速下降，在输注结束后至少10小时内，DNA合成仍被抑制在85%至95%。与治疗前测量的细胞水平相比，在输注开始后8小时，细胞嘌呤脱氧核苷酸池有所下降。结论：在10mg /m(2)/ min的固定给药速率下，吉西他滨可连续给药12小时以上，无不良反应。良好的毒性特征和药代动力学和药效学特征值得与dna损伤剂联合使用。(C) 2002年由美国临床肿瘤学会出版。
Purpose : To determine the maximum tolerated duration of infusions at the fixed gemcitabine dose rate of 10 mg/m(2)/min and to analyze the pharmacodynamic actions in leukemia blasts during gemcitabine therapy.Patients and Methods: The study was conducted in a phase I trial by escalating the duration of gemcitabine infusion at a fixed-dose rate of 10 mg/m(2) /min. Patients with relapsed or refractory acute myelogenous leukemia (AML) received gemcitabine for 8.0 (n = 3), 10.0 (n = 3), 12.5 (n = 8), 15.5 (n = 3), or 18.0 hours (n = 2). Pharmacokinetic and pharmacodynamic investigations were undertaken in circulating AML blasts.Results: Gemcitabine was infused for up to 18 hours at the fixed-close rate. Four patients had grade 3 toxicities at longer infusion schedules. One patient had a partial remission; two others had a reduction in blasts and concomitant rise in neutrophils. Gemcitabine triphosphate was detectable in AML cells even at 1 hour after the start of infusion in eight patients. The concentration ranged from 130 to 900 mumol/L at the end of the infusion. Consistently, there was a rapid decline in DNA synthesis, which remained suppressed at 85% to 95% during and for at least 10 hours after the end of the infusion. Compared with levels in cells measured before therapy, at 8 hours after the start of the infusion, there was a decline in the cellular purine deoxynucleotide pools.Conclusion: At the fixed-dose rate of 10 mg/m(2)/ min, gemcitabine could be administered for longer than 12 hours without untoward toxicity. The favorable toxicity profile and pharmacokinetic and pharmacodynamic features warrant combination with DNA-damaging agents. (C) 2002 by American Society of Clinical Oncology.