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首页> 外文期刊>Archives of Toxicology >Current limitations and future opportunities for prediction of DILI from in vitro
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Current limitations and future opportunities for prediction of DILI from in vitro

机译：当前限制和未来的体外预测帝力的机会

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Drug-induced liver injury (DILI) is a major concern for drug developers, regulators and clinicians. It is triggered by drug and xenobiotic insults leading to liver impairment or damage, in the worst-case liver failure. In contrast to acute "intrinsic" hepatotoxicity, DILI typically manifests in a very small subset of the population under treatment with no clear dose relationship and inconsistent temporal patterns and is therefore termed an idiosyncratic event. Involved are multifactorial, compound-dependent mechanisms and host-specific factors, making the prediction in preclinical test systems very challenging. While preclinical safety studies in animals usually are able to capture direct, acute liver toxicities, they are less predictive for human DILI, where specific, human-derived in vitro models can potentially close the gap. On one hand, mechanistic approaches addressing key mechanisms involved in DILI in well-characterized and standardized in vitro test systems have been developed. On the other hand, co-cultures of different cell types, including patient- and/or stem cell-derived cells, in a three-dimensional setup allow for prolonged incubations and multiplexed readouts. Such complex setups might better reflect multifactorial human DILI. One major challenge is that for many compounds with human DILI the underlying mechanisms are not yet fully understood, complicating establishment and validation of predictive cellular tools. A tiered approach including rapid mechanism-based in vitro screens followed by confirmatory tests in more physiologically relevant models might allow minimizing DILI risk early on in vitro. Such complex, integrated approaches will gain from larger collaborations in multidisciplinary groups bringing existing knowledge and state-of-the-art technology together.
机译：药物诱导的肝损伤（DILI）是药物开发商，监管机构和临床医生的主要关注点。在最坏情况下，它是由药物和异卵性侮辱引发导致肝脏损伤或损伤的损伤。与急性“内在”肝毒性相比，DiRi通常在群体的非常小的群体中表现出，没有明确的剂量关系和不一致的时间模式，因此被称为特质。所涉及的是多因素，复合依赖机制和宿主特定因素，使预测在临床前测试系统非常具有挑战性。虽然动物中的临床前安全性研究通常能够捕获直接，急性肝毒性，但它们对人体帝力的预测性较低，其中特定的人类衍生的体外模型可能临时缩小间隙。一方面，已经开发出寻址在体外测试系统中具有特征和标准化的DILI中涉及的关键机制的机械方法。另一方面，在三维设置中，在三维设置中包括患者和/或干细胞衍生细胞的不同细胞类型的共培养物允许长时间孵育和多路复用读出。这种复杂的设置可能更好地反映了多因素人体Dili。一个主要挑战是，对于许多具有人体Dili的化合物，潜在的机制尚不清楚，使预测性细胞工具的建立和验证复杂化。一种分层方法，包括基于快速机制的体外筛选，然后在更生理的相关模型中进行确诊试验可能允许在体外最小化在体外早期的风险。这些复杂的综合方法将从多学科群体中的较大合作，将现有的知识和最先进的技术在一起。

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