Roberts J T, Bleehen N M, Workman P, Walton M I
Int J Radiat Oncol Biol Phys. 1984 Sep;10(9):1755-8. doi: 10.1016/0360-3016(84)90543-1.
The 2-nitroimidazole hypoxic cell radiosensitizer Ro-03-8799 has been suggested to have possible advantages over misonidazole with regard both to radiosensitization and toxicity on the basis of reported experimental work. The present work reports a Phase I escalating dose toxicity study of the drug. This has shown severe acute central neurotoxicity at high dose levels (greater than 1 g/m2). Initial results of a multiple-dose toxicity study indicate that 1 g/m2 is likely to be the maximum dose which may be given repeatedly. The plasma and tumor pharmacokinetics of the drug have been measured. The mean t 1/2 for 9 patients was 5.8 +/- 1.5 hr. Peak plasma concentration is linearly related to dose and at 1 g/m2 is 12.1 +/- 2.3 micrograms/ml (n = 6). Human tumor drug concentrations have been measured after single doses of 1 g/m2 given to 8 patients with a variety of tumors. Peak tumor concentrations of drug of 11.7-81.6 micrograms/g were found. Because of acute, dose-limiting toxicity related to individual doses it may not be possible to achieve, in human tumors, concentrations of drug that offer significant advantage over misonidazole in terms of radiosensitizing efficiency. No evidence of chronic cumulative toxicity was observed at the doses employed.
据报道的实验研究表明，2-硝基咪唑类乏氧细胞放射增敏剂Ro-03-8799在放射增敏和毒性方面可能比甲硝唑具有优势。本研究报告了该药物的I期剂量递增毒性研究。结果显示，在高剂量水平（大于1 g/m²）时会出现严重的急性中枢神经毒性。多剂量毒性研究的初步结果表明，1 g/m²可能是可重复给药的最大剂量。已测定了该药物的血浆和肿瘤药代动力学。9名患者的平均t1/2为5.8±1.5小时。血浆峰值浓度与剂量呈线性相关，在1 g/m²时为12.1±2.3微克/毫升（n = 6）。对8名患有各种肿瘤的患者单次给予1 g/m²剂量后，测定了人体肿瘤中的药物浓度。发现肿瘤中药物的峰值浓度为11.7 - 81.6微克/克。由于与单次剂量相关的急性剂量限制性毒性，在人体肿瘤中可能无法达到在放射增敏效率方面比甲硝唑具有显著优势的药物浓度。在所使用的剂量下未观察到慢性累积毒性的证据。
