Ogawa M
Recent Results Cancer Res. 1980;70:45-51. doi: 10.1007/978-3-642-81392-4_4.
This paper reviews the methodology of phase I study in Japan. Most leading institutions participated in a phase I study when the decision was made to proceed with clinical trials after detailed analysis of experimental results of a new antitumor agent. An initial dose in phase I study used to be calculated according to the dose comparable to the minimum effective dose, 1/100 of LD 50 (mg/kg) in rodents, but the dose recently has been estimated based on one-tenth of mouse LD 10 (mg/m2) or one-third TLD in sensitive large animals. Qualitative prediction through preclinical toxicology indicated better correlation with clinically observed toxicities in gastrointestinal and hematopoietic systems, but renal and hepatic toxicities were being overestimated, and neurologic and skin toxicities were being underestimated. A recent trend in the development of new antitumor agents has been to find a less toxic and more effective compound. This has made phase I study more complicated, because metabolites produced in the midway of metabolic pathway might induce unprediced toxicities. Several approaches to conduct a phase I study more efficiently are discussed.
本文综述了日本I期研究的方法。在对一种新型抗肿瘤药物的实验结果进行详细分析后决定进行临床试验时，大多数主要机构都参与了I期研究。I期研究的初始剂量过去常根据与最小有效剂量相当的剂量来计算，即啮齿动物LD50（mg/kg）的1/100，但最近的剂量是根据小鼠LD10（mg/m2）的十分之一或敏感大型动物的三分之一TLD来估算的。通过临床前毒理学进行的定性预测表明，其与胃肠道和造血系统中临床观察到的毒性有更好的相关性，但肾毒性和肝毒性被高估，而神经毒性和皮肤毒性被低估。新型抗肿瘤药物开发的一个最新趋势是寻找毒性更小、效果更显著的化合物。这使得I期研究更加复杂，因为代谢途径中途产生的代谢产物可能会引发意想不到的毒性。本文讨论了几种更有效地进行I期研究的方法。
