Predictive Toxicology, Safety Assessment, Genentech, Inc., South San Francisco, CA, 94080, USA.
Non-Clinical Biostatistics, Product Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
Arch Toxicol. 2020 Sep;94(9):3185-3200. doi: 10.1007/s00204-020-02804-4. Epub 2020 Jun 24.
Drug-induced liver injury (DILI) continues to be a major cause of drug attrition and restrictive labeling. Given the importance of farnesoid X receptor (FXR) in bile acid homeostasis, drug-related FXR antagonism may be an important mechanism of DILI. However, a comprehensive assessment of this phenomenon broadly in the context of DILI is lacking. As such, we used an orthogonal approach comprising a FXR target gene assay in primary human hepatocytes and a commercially available FXR reporter assay to investigate the potential FXR antagonistic effects of an extensive test set of 159 compounds with and without association with clinical DILI. Data were omitted from analysis based on the presence of cytotoxicity to minimize false positive assay signals and other complications in data interpretation. Based on the experimental approaches employed and corresponding data, the prevalence of FXR antagonism was relatively low across this broad DILI test set, with 16-24% prevalence based on individual assay results or combined signals in both assays. Moreover, FXR antagonism was not highly predictive for identifying clinically relevant hepatotoxicants retrospectively, where FXR antagonist classification alone had minimal to moderate predictive value as represented by positive and negative likelihood ratios of 2.24-3.84 and 0.72-0.85, respectively. The predictivity did not increase significantly when considering only compounds with high clinical exposure (maximal or efficacious plasma exposures > 1.0 μM). In contrast, modest gains in predictive value of FXR antagonism were observed considering compounds that also inhibit bile salt export pump. In addition, we have identified novel FXR antagonistic effects of well-studied hepatotoxic drugs, including bosentan, tolcapone and ritonavir. In conclusion, this work represents a comprehensive evaluation of FXR antagonism in the context of DILI, including its overall predictivity and challenges associated with detecting this phenomenon in vitro.
药物性肝损伤（DILI）仍是药物淘汰和限制标签的主要原因。鉴于法尼醇 X 受体（FXR）在胆汁酸稳态中的重要性，药物相关的 FXR 拮抗作用可能是 DILI 的一个重要机制。然而，在 DILI 的广泛背景下，对这种现象进行全面评估还很缺乏。因此，我们使用了一种正交方法，包括在原代人肝细胞中的 FXR 靶基因测定和一种商业上可用的 FXR 报告基因测定，来研究广泛的测试组 159 种化合物的潜在 FXR 拮抗作用，这些化合物与临床 DILI 有关或无关。根据存在细胞毒性的数据从分析中省略，以尽量减少假阳性测定信号和数据解释中的其他并发症。根据所采用的实验方法和相应的数据，在这个广泛的 DILI 测试组中，FXR 拮抗作用的发生率相对较低，基于单个测定结果或两个测定中的组合信号，发生率为 16-24%。此外，FXR 拮抗作用并不能高度预测回顾性地识别临床上相关的肝毒物，其中 FXR 拮抗剂分类本身的预测值很小到中等，阳性和阴性似然比分别为 2.24-3.84 和 0.72-0.85。当仅考虑具有高临床暴露（最大或有效血浆暴露>1.0μM）的化合物时，预测能力并没有显著增加。相比之下，当考虑也抑制胆汁盐输出泵的化合物时，FXR 拮抗作用的预测价值有适度增加。此外，我们还发现了一些研究充分的肝毒性药物的新型 FXR 拮抗作用，包括波生坦、托卡朋和利托那韦。总之，这项工作代表了在 DILI 背景下对 FXR 拮抗作用的全面评估，包括其整体预测能力和在体外检测这种现象的相关挑战。
