Amouzadeh Hamid R, Dimery Isaiah, Werner Jonathan, Ngarmchamnanrith Gataree, Engwall Michael J, Vargas Hugo M, Arrindell Deborah
Immuno-Oncology Therapeutic Area Safety, Global Patient Safety, Labeling and Pediatrics, Amgen Inc., Thousand Oaks, CA, 91320, USA.
Immuno-Oncology Therapeutic Area Safety, Global Patient Safety, Labeling and Pediatrics, Amgen Inc., Thousand Oaks, CA, 91320, USA.
Transl Oncol. 2019 Oct;12(10):1296-1304. doi: 10.1016/j.tranon.2019.05.018. Epub 2019 Jul 19.
Off-target activities of drug candidates observed during in vitro pharmacological profiling frequently do not translate to adverse events (AEs) in human. This could be because off-target activities do not have functional consequences, are not observed at exposures achieved during clinical testing, or may not translate into clinical outcomes. We report clinical consequences of an off-target activity observed during profiling of AMG 337, a selective inhibitor of the mesenchymal-epithelial transition factor being evaluated for treatment of solid tumors. In our screen of 151 potential off-targets, AMG 337 inhibited only adenosine transporter (AT). During clinical trials, headache emerged as the dose-limiting AE in the first-in-human trial. It was thought that headache was caused by extracellular accumulation of adenosine from inhibition of AT by AMG 337 and subsequent adenosine-mediated vasodilation through adenosine receptors (ARs). Further nonclinical studies were performed to evaluate this hypothesis. AMG 337 inhibited AT function in dog and human cells in vitro and dog and human arteries ex vivo. In a dog telemetry study, AMG 337 caused hypotension, which was reduced by pretreatment with theophylline, an AR antagonist. Overall, nonclinical and clinical data suggested that headache was due to cerebral vasorelaxation caused by AMG 337-mediated inhibition of AT. When subjects were advised to drink coffee, an AR antagonist, prior to AMG 337, the severity of headaches was reduced, allowing them to continue treatment. These findings demonstrate the importance of carefully evaluating clinical observations during early drug development and the value of translational nonclinical studies to investigate the mechanism of action driving clinical observations.
在体外药理学分析过程中观察到的候选药物的脱靶活性，在人体中往往不会转化为不良事件（AE）。这可能是因为脱靶活性没有功能后果，在临床试验达到的暴露水平下未被观察到，或者可能不会转化为临床结果。我们报告了在AMG 337分析过程中观察到的一种脱靶活性的临床后果，AMG 337是一种正在评估用于治疗实体瘤的间充质-上皮转化因子的选择性抑制剂。在我们对151个潜在脱靶标的筛选中，AMG 337仅抑制腺苷转运体（AT）。在临床试验中，头痛成为首次人体试验中的剂量限制性AE。人们认为头痛是由于AMG 337抑制AT导致腺苷在细胞外积累，随后通过腺苷受体（ARs）介导的腺苷血管舒张所致。进行了进一步的非临床研究以评估这一假设。AMG 337在体外抑制犬和人细胞以及离体犬和人动脉中的AT功能。在一项犬遥测研究中，AMG 337导致低血压，用AR拮抗剂茶碱预处理可减轻这种情况。总体而言，非临床和临床数据表明头痛是由AMG 337介导的AT抑制引起的脑血管舒张所致。当建议受试者在服用AMG 337之前喝咖啡（一种AR拮抗剂）时，头痛的严重程度降低，使他们能够继续治疗。这些发现证明了在药物早期开发过程中仔细评估临床观察结果的重要性，以及转化性非临床研究对于研究驱动临床观察结果的作用机制的价值。
