基于证据权重的新方法方法来确认药物的发育毒性
Natasha R Catlin1, Gregg D Cappon2, Scott D Davenport1
1Drug Safety Research and Development, Pfizer Research & Development, Groton, CT, USA.
Reproductive toxicology (Elmsford, N.Y.)
|August 11, 2024
概括
对于发育性毒性 (DevTox NAMs) 的新方法方法 (NAMs) 可以增强药物安全性评估. 这些方法补充了传统的动物研究,改善了对胎儿伤害风险的理解.
科学领域:
- 药理学和毒理学 药理学和毒理学
- 生殖和发育毒理学
- 在体外毒理学中
背景情况:
- 传统的胚胎胎发育毒性评估严重依赖于动物研究.
- 国际指导方针 (ICH S5R3) 鼓励整合替代测定和证据权重 (WoE) 以减少动物使用.
- 在将替代测定结果转化为体内效应和人类相关性方面仍然存在挑战.
研究的目的:
- 评估开发性毒性 (DevTox NAMs) 的新方法方法的预测性.
- 为了说明DevTox NAMs在补充证据权重 (WoE) 评估中的价值.
- 通过使用制药实例,检查NAM和体内研究中的度-效应水平之间的关系.
主要方法:
- 作为案例研究,使用了两种药物化合物 (glasdegib和lorlatinib).
- 采用了一系列体外测试,包括mEST,rWEC,斑马鱼和基于人类的干细胞.
- 从DevTox NAM中集成的数据与现有的基于文献的WoE和初步的胚胎胎发育数据.
主要成果:
- 来自测试试验的体外结果证实了对所选化合物的现有证据的权重.
- 初步的胚胎胎发育数据进一步证实了DevTox NAMs的发现.
- 证明了DevTox NAMs与传统的毒性评估数据保持一致并增强其能力.
结论:
- DevTox NAMs在补充发育毒性的传统证据权重方法方面表现有希望.
- 这些数据支持将DevTox NAM集成到药物发育毒性评估中,特别是对于晚期癌症的指示.
- 这些替代方法可以帮助减少动物使用,同时告知怀孕不良结果的潜在风险.
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