目的:特异性药物性肝损伤(DILI)是由药物引起的复杂且不可预测的事件,草药或膳食补充剂。在临床前阶段早期识别人类肝毒性仍然是一个主要挑战。其中选择经过验证的体外系统和测试药物具有重大影响。本系统综述分析了肝毒性测定中使用的化合物,并建立了DILI阳性和阴性对照药物列表,用于验证DILI的体外模型。得到文献和临床证据的支持,并得到COSTActionProEuroDILINetwork(CA17112)专家委员会的认可。
方法:遵循2020年PRISMA指南,专注于DILI的原始研究文章,其使用体外人类模型并使用阳性和阴性对照化合物进行至少一种肝毒性测定,包括在内。通过改良的“毒理学数据可靠性评估工具”评估了研究的偏差。
结果:51项研究(2,936项)符合纳入标准,有30个被归类为可靠的,没有限制。尽管对阳性化合物有广泛的共识,阴性化合物的选择缺乏清晰度。2D单文化,短的暴露时间和细胞毒性终点是测试最多的,尽管在药物浓度上没有达成共识。
结论:广泛的分析强调了对于体外DILI评估的对照化合物缺乏一致意见。在全面的体外和临床数据分析以及专家委员会的意见之后,提出了10种阳性和阴性药物的循证共识驱动列表,用于验证体外模型,以改善临床前药物安全性检测制度.
■在药物开发过程的早期预测人类毒性仍然是一个重大挑战。为此,人体体外模型变得越来越重要,然而,开发更多生理相关的肝脏模型和仔细选择对照DILI+和DILI-药物是更好地预测新候选药物的DILI责任的必要条件。因此,这项系统研究对于用于研究药物诱导的肝损伤(DILI)的新体外模型的标准化验证具有重要意义.通过建立共识驱动的阳性和阴性对照药物清单,该研究为增强临床前测试的一致性提供了一个科学合理的框架,从而解决了早期肝毒性鉴定的重大挑战。结果对参与药物开发过程的所有行为者至关重要,提供评估肝毒性风险的标准化方法。实际上,这些发现可以指导研究人员评估新药的安全性,精制体外模型,并向监管机构通报监管准则的潜在改进,确保更系统和有效的药物安全性评估方法。
OBJECTIVE: Idiosyncratic drug-induced liver injury (DILI) is a complex and unpredictable event caused by drugs, and herbal or dietary supplements. Early identification of human hepatotoxicity at preclinical stages remains a major challenge, in which the selection of validated in vitro systems and test drugs has a significant impact. In this systematic review, we analyzed the compounds used in hepatotoxicity assays and established a list of DILI-positive and -negative control drugs for validation of in vitro models of DILI, supported by literature and clinical evidence and endorsed by an expert committee from the COST Action ProEuroDILI Network (CA17112).
METHODS: Following 2020 PRISMA
guidelines, original research articles focusing on DILI which used in vitro human models and performed at least one hepatotoxicity assay with positive and negative control compounds, were included. Bias of the studies was assessed by a modified \'Toxicological Data Reliability Assessment Tool\'.
RESULTS: A total of 51 studies (out of 2,936) met the inclusion criteria, with 30 categorized as reliable without restrictions. Although there was a broad
consensus on positive compounds, the selection of negative compounds lacked clarity. 2D monoculture, short exposure times and cytotoxicity endpoints were the most tested, although there was no
consensus on drug concentrations.
CONCLUSIONS: Extensive analysis highlighted the lack of agreement on control compounds for in vitro DILI assessment. Following comprehensive in vitro and clinical data analysis together with input from the expert committee, an evidence-based consensus-driven list of 10 positive and negative control drugs for validation of in vitro models of DILI is proposed.
UNASSIGNED: Prediction of human toxicity early in the drug development process remains a major challenge, necessitating the development of more physiologically relevant liver models and careful selection of drug-induced liver injury (DILI)-positive and -negative control drugs to better predict the risk of DILI associated with new drug candidates. Thus, this systematic study has crucial implications for standardizing the validation of new in vitro models of DILI. By establishing a
consensus-driven list of positive and negative control drugs, the study provides a scientifically justified framework for enhancing the consistency of preclinical testing, thereby addressing a significant challenge in early hepatotoxicity identification. Practically, these findings can guide researchers in evaluating safety profiles of new drugs, refining in vitro models, and informing regulatory agencies on potential improvements to regulatory
guidelines, ensuring a more systematic and efficient approach to drug safety assessment.