非临床心血管安全测试:现状,差距和新兴趋势
Peter Hoffmann1, Michael K Pugsley2
1Independent Consultant, Beaufort, SC 29907, USA.
Journal of pharmacological and toxicological methods
|October 24, 2025
概括
目前对心血管不良反应的药物安全性测试有限,经常缺少关键风险. 推进非临床方法对于检测更广泛的心脏责任和提高药物安全至关重要.
科学领域:
- 药理学 药理学是指药理学的学科.
- 毒理学 毒理学 毒理学
- 心血管科学 心血管科学
背景情况:
- 心血管药物不良反应 (cADRs) 是药物消耗的主要原因,通常在开发或营销后晚期检测到.
- 目前的非临床安全测试,专注于QT延长和IKr抑制,可能会忽视其他心血管负债.
- 现有的监管框架 (ICH S7A/S7B) 在很大程度上依赖于核心电池研究,而后续机制不足.
研究的目的:
- 审查目前非临床心血管安全评估的局限性.
- 突出非临床发现和临床/营销后cADRs之间的差距.
- 为全面的心血管风险评估提出非临床方法的进展.
主要方法:
- 审查目前的非临床心血管安全测试范式.
- 监管指南中的局限性分析 (ICH S7A/S7B).
- 讨论新出现的趋势,包括先进的体外/体内模型和机械终点.
主要成果:
- 目前的方法显示过度依赖特定的测试 (例如,QT延长) 和不够的机械深度.
- 在非临床预测和观察到的临床心血管不良事件之间存在显著的差距.
- 需要更好地检测对心脏节律,收缩性,血压和血栓发生率的影响.
结论:
- 非临床心血管安全评估需要比目前的核心电池研究更进一步.
- 整合功能和机械终点对于更好的翻译相关性至关重要.
- 需要对监管框架进行重新评估,以更有效地应对各种心血管风险.
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