使用创新的体外肝脏模型进行基于机制的药物安全测试:从DILI预测到特异性的DILI责任评估
Sibel Bahtiri1, Tessa M S Hagens1, Bob van de Water1
1Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
Expert opinion on drug metabolism & toxicology
|June 6, 2025
概括
预测特异性药物诱导性肝损伤 (iDILI) 是一个挑战. 本综述评估了用于药物开发中的早期iDILI风险评估的体外模型和机械读数.
科学领域:
- 药理学 药理学是指药理学的学科.
- 毒理学 毒理学 毒理学
- 药物开发 药物开发
背景情况:
- 非同步性药物诱导性肝损伤 (iDILI) 是不可预测的,影响了很少一部分患者,并导致晚期药物失败.
- 早期识别iDILI负债对于降低成本和降低患者风险至关重要.
研究的目的:
- 审查iDILI风险因素的最新文献 (过去5年).
- 评估用于iDILI责任评估的体外肝脏模型和基于机制的读数的潜力.
主要方法:
- 在PubMed的文献中搜索过去5年发表的文章.
- 评估各种体外肝脏模型用于疾病建模和DILI预测.
- 对iDILI责任的基于机制的读取策略的评估.
主要成果:
- 当前的体外肝脏模型存在缺点,需要对其应用进行仔细评估.
- 建议采用使用简单模型的分层方法,然后采用具有机械读数的多细胞模型.
- 综合战略中的多重化模型可以提高安全评估的准确性.
结论:
- 定义的体外模型应纳入肝细胞内在的风险因素和适应性免疫组件.
- 完善iDILI责任评估需要将iDILI发病的知识与机械读取结合起来.
- 一个全面的,基于机制的测试策略是提高药物安全的关键.
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