与5-HT2B激动因子相关的心脏膜病变的临床前缓解重新审视
Bérengère M Dumotier1, Laszlo Urban2
1Novartis Biomedical Research, Translational Medicine, Preclinical Safety, Basel CH-4056, Switzerland.
Journal of pharmacological and toxicological methods
|July 20, 2024
概括
预测药物开发中的心脏膜病变风险需要评估5-基三胺 (5-HT) 2B受体活性. 持续的血暴露 (AUC),而不是峰值水平 (Cmax),准确地区分药物与临床心脏门疾病风险.
科学领域:
- 药理学和毒理学 药理学和毒理学
- 药物开发与安全问题
背景情况:
- 与5-二三胺 (5-HT) 2B受体激活相关的心脏门病 (CVD) 是药物开发中的已知风险.
- 目前的监管指南使用了5-HT2B结合数据和Cmax作为安全边际,但预测仍然具有挑战性.
研究的目的:
- 为药物诱导心血管疾病风险的临床前预测提供增强的建议.
- 为了完善对与药物暴露相关的5-HT2B受体活性评估,以评估安全性.
主要方法:
- 从具有和没有5-HT2B活性的药物中分析临床前和临床的药理学和药理动力学数据.
- 在体外对持续性血暴露 (AUCs) 与峰值暴露 (Cmax) 的5-HT2B激动剂亲和力的比较.
主要成果:
- 与持续性血暴露 (AUCs) 相结合的5-HT2B激动剂亲和力为计算安全边际提供了更准确的基础.
- 这种方法有效地区分了具有临床心血管疾病风险的药物和没有药物的药物,即使有一些5-HT2B活性.
- 同时强调了与5-HT2B激动剂相关的多器官纤维化风险,这种风险往往被低估.
结论:
- 使用持续性血暴露 (AUC) 与5-HT2B功能测定数据一起,可以改善临床前心血管疾病风险预测.
- 建议旨在在临床药物开发过程中减轻与心血管疾病和纤维化相关的风险.
- 这种精细的方法提高了针对或与5-HT2B受体相互作用的候选药物的安全性评估.
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