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针对中枢神经系统疾病的反感性寡核酸的多种最小生理学基础的药理学-药理学模型

Devam A Desai¹, Mfonabasi E Ette¹, Dhaval K Shah¹

¹Division of Pharmacokinetics-Pharmacodynamics and Systems Pharmacology, Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York.

Drug metabolism and disposition: the biological fate of chemicals

|October 16, 2025

概括

这项研究开发了一种定量模型,用于预测跨物种中枢神经系统中的反感性寡核酸 (ASO) 药物效应. 该模型有助于将临床前数据转化为ASO疗法的人类临床试验.

科学领域:

药理学和毒理学药理学和毒理学
生物技术和基因工程生物技术和基因工程

背景情况:

反感性寡核酸 (ASO) 是一种有针对性的疗法,通过抑制mRNA来降低蛋白质水平.
将ASO临床前数据转化为人类临床结果需要强大的药理动力学-药理动力学 (PK-PD) 模型.

研究的目的:

开发一个定量,多种框架来描述ASO在中枢神经系统 (CNS) 的处置和影响.
为了便于将临床前ASO药理学转化为临床应用.

主要方法:

为ASOs开发了一个基于最小生理学的药理动力学-药理动力学 (PK-PD) 模型.
综合公布的药物和特定物种的生理数据,包括PK和mRNA表达.
纳入的关键过程:内细胞分裂,外细胞分裂,新陈代谢,巨细胞分裂和蛋白质淘汰.

主要成果:

该模型成功捕获了临床前物种 (老鼠,大鼠,子) 和人类儿科试验对象的ASO的PK数据.
测量尺度缩放和最小的基于生理学的PK概念被用来描述ASO跨物种的生物分布.
确定了影响CNS ASO PK-PD属性的关键处置过程.

结论:

开发的翻译PK-PD模型增强了对人类大脑和血中ASO药物暴露的预测.
该模型支持用于ASO治疗的化合物选择,剂量预测和早期临床PK-PD数据的解释.
这一框架促进了ASO的中枢神经系统向基因疗法和精准医学应用.

关键词:

反意义的寡核化物.人类人类人类人类人类药理动力学是什么药理动力学药理动力学药理动力学基于生理学的药理动力学.临床前临床前

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