Pfizer Global Research & Development, Pharmacokinetics, Dynamics & Metabolism, Andover, MA 01810, USA.
Biomark Med. 2010 Jun;4(3):475-83. doi: 10.2217/bmm.10.9.
Certain compounds that induce liver injury clinically are not readily identified from earlier preclinical studies. Novel biomarkers are being sought to be applied across the pharmaceutical pipeline to fill this knowledge gap and to add increased specificity for detecting drug-induced liver injury in combination with aminotransferases (alanine and aspartate aminotransferase)--the current reference-standard biomarkers used in the clinic. The gaps in the qualification process for novel biomarkers of regulatory decision-making are assessed and compared with aminotransferase activities to guide the determination of safe compound margins for drug delivery to humans where monitoring for potential liver injury is a cause for concern. Histopathologic observations from preclinical studies are considered the principal reference standard to benchmark and assess subtle aminotransferase elevations. This approach correlates quite well for many developmental compounds, yet cases of discordance create dilemmas regarding which standard(s) indicates true injury. Concordance amongst a broader set of biomarker injury signals in a qualification paradigm will increase confidence, leading to accepted and integrated translational biomarker signals during safety assessment processes across the pharmaceutical industry, with academia, in government and in contractor laboratories.
某些在临床上会引起肝损伤的化合物在早期的临床前研究中不容易被识别。目前正在寻找新的生物标志物，以应用于整个药物研发过程中，以填补这一知识空白，并增加对药物性肝损伤的检测特异性，同时结合转氨酶（丙氨酸和天冬氨酸转氨酶）——目前临床上使用的参考标准生物标志物。本文评估了监管决策新型生物标志物的资格过程中的差距，并与转氨酶活性进行了比较，以指导确定安全的化合物剂量，用于向人体输送药物，因为对潜在肝损伤的监测是一个关注的问题。临床前研究中的组织病理学观察被认为是基准和评估轻微转氨酶升高的主要参考标准。这种方法与许多发育化合物相关性很好，但不一致的情况会导致关于哪个标准（或多个标准）指示真正损伤的难题。在资格模式中，更广泛的生物标志物损伤信号的一致性将提高信心，从而在药物研发行业、学术界、政府和合同实验室的安全评估过程中，接受和整合可转化的生物标志物信号。
