药物发育毒性体外替代方法研究进展及组合策略

Research progress and integrated testing strategies on alternative methods in drug developmental toxicity evaluation

随着3Rs原则的实施,药物非临床生殖发育毒性研究中的整体动物试验面临严重挑战,体外替代研究逐步成为研究热点。生殖发育毒性周期长,涵盖面广,现有的任何一种体外方法无法全面模拟药物在体内作用的全过程,无法全面反映其对于生殖发育周期中性成熟、受精、配子发生、合子发育、出生后发育及性功能等方面的影响。形成一套完整的生殖发育毒性体外替代法评价是解决体外替代法预测结果接近体内检测结果的关键,在整合体外替代研究时,应考虑体细胞与生殖细胞,不同进化阶段的物种,多个生殖毒性周期,体内外代谢活化差异等因素。根据受试物特性、分布、用途、适用范围,其他毒理学实验及毒代动力学资料,技术水平,管理部门的要求等特点进行实验设计,通过一系列反应不同试验终点的组合实验(Integrated testing strategy,ITS)综合评定药物体外生殖发育毒性,但目前尚无最合理的组合方案。对生殖发育毒性体外试验研究进展及应用策略需考虑要点进行综述,以推动替代技术在药物非临床安全性评价中的应用。

With the implementation of the 3Rs principle, the non-clinical reproductive and developmental toxicity studies of drugs in experimental animals are facing great challenges. Due to the long period of reproductive and developmental toxicity, any of the existing in vitro method cannot fully simulate the whole process of drug action in vivo. The existing methods cannot fully reflect the development cycle for reproductive neutral maturation, fertilization, zygote development, impact of development and other aspects of sexual function after birth. It is necessary to form a complete set of alternative method for reproductive and developmental toxicity in vitro evaluation to solve the above problems. To design an integrate research of in vitro alternative methods, the researchers should consider somatic and germ cells in different stages of the evolution of species, a number of reproductive toxicity periods, in vivo metabolic activation differences, and other factors. According to characteristics, distribution, use, scope, other toxicology experiments and toxic kinetic information, technology, management and other characteristics of the test substance, the experiment design requires a series of reactions with different combinations of experimental study endpoint （integrated testing strategy, ITS） of comprehensive assessment of reproductive and developmental toxicity in vitro drug. There is no combination of the most reasonable scheme available. In this paper, we will discuss the latest progress of in vitro studies and how to promote a battery of alternative technology of developmental and reproductive toxicity in the pharmaceutical non-clinical safety evaluation.