跨物种大脑PBPK建模平台,预测通过血脑屏障的被动运输,并评估目标位置的配置
Parsshava Mehta1, Amira Soliman1,2, Leyanis Rodriguez-Vera3
1Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL 32827, USA.
Pharmaceutics
|February 24, 2024
概括
基于生理学的药理动力学 (PBPK) 模型可以预测中枢神经系统 (CNS) 中的药物度. 这种工具有助于开发新的中枢神经系统药物,通过评估它们穿越血脑屏障 (BBB) 的能力.
科学领域:
- 药理动力学和药物开发
- 神经科学和中枢神经系统 (CNS) 研究
- 计算机生物学和建模
背景情况:
- 中枢神经系统药物开发中的高失败率与对目标部位药物暴露的理解不足有关.
- 需要有效的工具来评估中枢神经系统候选药物的血脑屏障 (BBB) 透性.
- 基于生理学的药理动力学 (PBPK) 模型整合了药物和系统特征,以预测点分布.
研究的目的:
- 为预测中枢神经系统药物度的PBPK平台模型提供资格.
- 评估模型的实用性,当人类数据稀缺,传送器活动最小时.
- 建立一个可靠的工具,用于中枢神经系统药物开发和剂量评估.
主要方法:
- 在老鼠和人类中收集了关于乙氨基,氧化,胺,布洛芬和 levetiracetam 的文献数据.
- 从使用跨物种BBB表面积差异的老鼠数据中推断出人类BBB透率.
- 利用PBPK平台模型来模拟和预测中枢神经系统中的药物度.
主要成果:
- 该PBPK模型在预测中枢神经系统药物度方面取得了高准确性,在AUC和Cmax的1.25倍标准内,预测率为85% (老鼠) 和100% (人类).
- 在所有测试药物和物种中,整体几何平均折叠误差 (GMFE) 低于1.25.
- 证明成功地预测了人类中枢神经系统度的药物被动穿越BBB.
结论:
- PBPK平台是一个经过验证的工具,用于预测被动分布药物的人类中枢神经系统药物度.
- 这种模型可以帮助在开发早期选择有前途的中枢神经系统候选药物.
- PBPK平台可以为评估现有中枢神经系统药物的新剂量方案提供信息.
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