Chalasani Naga, Hayashi Paul H, Luffer-Atlas Debra, Regev Arie, Watkins Paul B
Indiana University School of Medicine, Indianapolis, Indiana, USA.
Office of New Drugs, United States Food and Drug Administration, Silver Spring, Maryland, USA.
Hepatology. 2025 Feb 25. doi: 10.1097/HEP.0000000000001281.
DILI is rare in clinical practice, but when it occurs, it can lead to acute liver failure and death. Drug developers and regulators undertake a series of steps to identify the DILI potential of a medication before it is approved for marketing. Preclinical testing by drug developers typically involves a multitude of in vitro assays and in vivo animal experiments before a compound is moved into first-in-human phase 1 testing. Over the last 2 decades, there have been a number of advances in preclinical screening for DILI potential of a new chemical entity, but these approaches tend to be overly sensitive with insufficient positive predictive value. Once in clinical trials, the DILI potential of an investigational agent and risks to a participant are carefully managed through patient selection, DILI monitoring paradigms, and drug interruption and discontinuation criteria, in close concert with the regulators. Recent developments in quantitative systems toxicology offer promising and complementary in silico approaches to predict the compound's risk for DILI via multifaceted systems biology. When a drug developer submits a New Drug Application for marketing approval, regulators review the preclinical and clinical trial data in a structured fashion to assess the DILI risk. While these approaches have been successful in dramatically reducing the marketing approval of medications eventually associated with hepatotoxicity, many challenges remain in identifying the risk for DILI during preclinical and early-to-late clinical development stages for genetic medicines, biological agents, and immunotherapies. In this review, we discuss current preclinical, in-silico, and clinical development approaches to screen for the DILI potential of an investigational agent and provide a high-level description of regulators' approach for assessing DILI risk in a New Drug Application.
药物性肝损伤（DILI）在临床实践中较为罕见，但一旦发生，可能导致急性肝衰竭甚至死亡。药物研发人员和监管机构在药物获批上市前会采取一系列措施来识别其引发DILI的可能性。药物研发人员进行的临床前测试通常在化合物进入人体首次1期试验之前，涉及大量的体外试验和体内动物实验。在过去20年里，针对新化学实体引发DILI可能性的临床前筛查取得了一些进展，但这些方法往往过于敏感，阳性预测值不足。一旦进入临床试验，研究药物引发DILI的可能性以及对受试者的风险会通过患者选择、DILI监测模式以及药物中断和停药标准，并与监管机构密切配合进行仔细管理。定量系统毒理学的最新进展提供了有前景且互补的计算机模拟方法，通过多方面的系统生物学来预测化合物引发DILI的风险。当药物研发人员提交新药上市申请时，监管机构会以结构化方式审查临床前和临床试验数据，以评估DILI风险。虽然这些方法已成功大幅减少最终与肝毒性相关药物的上市批准，但在识别基因药物、生物制剂和免疫疗法的临床前及临床早期到晚期开发阶段的DILI风险方面，仍存在许多挑战。在本综述中，我们讨论了当前用于筛查研究药物引发DILI可能性的临床前、计算机模拟和临床开发方法，并简要介绍了监管机构在新药申请中评估DILI风险的方法。
