Regev Arie
Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana.
Semin Liver Dis. 2014 May;34(2):227-39. doi: 10.1055/s-0034-1375962. Epub 2014 May 31.
Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drug's potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development.
尽管正在进行深入研究，但药物性肝损伤（DILI）对医疗服务提供者和患者来说仍然是一个严重问题，并且在过去50年中一直是药物撤市和监管机构不予批准的主要原因。因此，DILI仍然是制药行业的主要担忧，也是药物研发过程中导致药物淘汰的主要原因。在大多数情况下，严重的DILI是一种罕见的特异质性反应，通常在药物研发的临床前阶段或早期临床阶段不会出现。在大多数案例中，在人体中导致严重DILI的药物在包括动物研究、细胞培养或其他方法在内的临床前评估中并未显示出明确且一致的肝毒性信号。尽管人们付出了巨大努力来开发更好的生物标志物，以帮助在药物研发的早期阶段预测DILI风险，但目前此类生物标志物缺乏充分证据支持，药物制造商也无法常规使用。由于在药物研发的临床前阶段缺乏有效且准确的方法来预测特异质性DILI，不同的药物制造商采用了不同的方法，而这些方法往往缺乏强有力的系统证据支持。基于越来越多的经验，越来越明显的是，在临床研发过程中发生的较轻形式的肝损伤，若评估正确，可能会显著提高我们预测药物上市后导致更严重肝损伤的潜力的能力。许多药物制造商已经采用了基于这一概念的策略，并且在药物研发过程中越来越多地予以实施。对个别肝脏病例进行细致的因果关系评估并遵守严格的肝脏停药规则是该方法的关键组成部分，并且必须依靠全面的临床评估，偶尔还需由在DILI和药物研发方面经验丰富的肝脏专家进行评估。
