Nemoto K, Shibamoto Y, Ohmagari J, Baba Y, Ebe K, Ariga H, Takai Y, Ouchi A, Sasai K, Shinozaki M, Tsujitani M, Sakaguchi M, Yamada S, Sakamoto K
Department of Radiology, Tohoku University Hospital, Sendai, Japan.
Anticancer Drugs. 2001 Jan;12(1):1-6. doi: 10.1097/00001813-200101000-00001.
A phase Ia study of a 2-nitroimidazole nucleoside analog radiosensitizer doranidazole was conducted to evaluate its toxicity and pharmacokinetics in patients undergoing conventional external beam radiotherapy. Twenty-nine patients, aged 40-74 years, with a WHO performance status of 0-2 and with adequate organ functions, were entered in the study. Single administration of doranidazole was investigated first with 13 patients and then a course of five consecutive daily administrations was tested in 16 patients. Doranidazole was given i.v. 25 min before irradiation. Doranidazole doses of 400, 800, 1300 and 2000 mg/m2 were evaluated in the former study, and daily doses of 800, 1300 and 2000 mg/m2 were investigated in the latter study. All patients tolerated doranidazole administration. Although a transient decrease in the 24-h creatinine clearance rate was observed in five patients (one in the single administration study and four in the repeat administration study), this was not considered to be the dose-limiting toxicity. Other toxicities (hematological and gastrointestinal), which may not be related to doranidazole administration, were also mild and were not dose limiting. No neurotoxicity was observed. The average maximum concentration, area under the time-concentration curve and half-life of doranidazole in serum were 172-194 microg/ml, 502-582 microg x h/l and 4.2-4.6 h, respectively, at 2000 mg/m2. At the tested doses, administration of doranidazole was tolerable and achieved serum concentrations at which reasonable radiosensitization could be expected. A phase Ib/II study to evaluate the feasibility and efficacy of up to 30 repeat administrations seems to be warranted.
开展了一项关于2-硝基咪唑核苷类似物放射增敏剂多拉硝唑的Ia期研究，以评估其在接受常规外照射放疗患者中的毒性和药代动力学。29例年龄在40至74岁之间、世界卫生组织体能状态为0至2且器官功能良好的患者进入该研究。首先对13例患者进行了多拉硝唑单次给药研究，然后对16例患者进行了连续5天每日给药的疗程测试。多拉硝唑在放疗前25分钟静脉注射。在前一项研究中评估了400、800、1300和2000mg/m²的多拉硝唑剂量，在后一项研究中研究了800、1300和2000mg/m²的每日剂量。所有患者均耐受多拉硝唑给药。尽管在5例患者中观察到24小时肌酐清除率短暂下降（单次给药研究中有1例，重复给药研究中有4例），但这未被视为剂量限制性毒性。其他可能与多拉硝唑给药无关的毒性（血液学和胃肠道毒性）也较轻，且不是剂量限制性的。未观察到神经毒性。在2000mg/m²剂量下，多拉硝唑在血清中的平均最大浓度、时间-浓度曲线下面积和半衰期分别为每毫升172至194微克、502至582微克·小时/升和4.2至4.6小时。在所测试的剂量下，多拉硝唑给药耐受性良好，并达到了预期可产生合理放射增敏作用的血清浓度。开展一项Ib/II期研究以评估多达30次重复给药的可行性和疗效似乎是有必要的。
