Coleman C N, Urtasun R C, Wasserman T H, Hancock S, Harris J W, Halsey J, Hirst V K
Int J Radiat Oncol Biol Phys. 1984 Sep;10(9):1749-53. doi: 10.1016/0360-3016(84)90542-x.
From March 15, through August 31, 1983, 37 patients have been entered on the RTOG Phase I trial of SR-2508. The drug was given intravenously three times weekly for three weeks. The starting total dose was 11.7 g/m2 and the highest total dose given was 32 g/m2. The lower lipophilicity of SR-2508 has produced the expected decrease in terminal half-life (5.4 hrs) of drug excretion and increase in total drug excreted unchanged in the urine (71%) compared to misonidazole or desmethylmisonidazole. The maximum single dose (3.7 g/m2) administered was well tolerated. With multiple doses peripheral neuropathy is the dose-limiting toxicity. The lowest cumulative dose producing toxicity was 21.6 g/m2, the highest non-toxic dose was 29.7 g/m2. The use of an individual patient's drug exposure as measured by the area under the curve of drug concentration vs time may be an excellent predictor of toxicity. This may eventually permit individualization of dose and prevention of serious toxicity. A single dose of 2 g/m2 will produce a tumor concentration of drug (approx. 100 micrograms/ml) that will yield a sensitizer enhancement ratio of 1.5 to 1.7. Using a starting dose of 2 g/m2 three times weekly, patients are now being studied on a five week drug schedule to further evaluate predictability of drug toxicity in preparation for clinical trials of drug efficacy.
从1983年3月15日至8月31日，37例患者参加了放射肿瘤学研究组（RTOG）的SR - 2508一期试验。药物每周静脉注射三次，共三周。起始总剂量为11.7 g/m²，最高总剂量为32 g/m²。与米索硝唑或去甲基米索硝唑相比，SR - 2508较低的亲脂性导致药物排泄的终末半衰期预期缩短（5.4小时），且尿液中未改变排泄的药物总量增加（71%）。最大单次剂量（3.7 g/m²）给药后耐受性良好。多次给药时，周围神经病变是剂量限制性毒性。产生毒性的最低累积剂量为21.6 g/m²，最高无毒剂量为29.7 g/m²。通过药物浓度与时间曲线下面积测量的个体患者药物暴露情况可能是毒性的良好预测指标。这最终可能允许剂量个体化并预防严重毒性。2 g/m²的单次剂量将产生肿瘤药物浓度（约100微克/毫升），其致敏增强比为1.5至1.7。以每周三次2 g/m²的起始剂量，目前正在对患者进行为期五周的用药方案研究，以进一步评估药物毒性的可预测性，为药物疗效的临床试验做准备。
