开放系统药理学套件的全球敏感性分析基于生理学的药理动力学模型
Abdulkarim Najjar1, Abdullah Hamadeh2,3, Sophia Krause1
1Beiersdorf AG, Hamburg, Germany.
CPT: pharmacometrics & systems pharmacology
|November 5, 2024
概括
本研究引入了一套软件包,用于在生理学基础药理动力学 (PBPK) 模型中进行灵敏度分析. 该工具有助于评估参数不确定性和可变性,这对于监管提交和模型优化至关重要.
科学领域:
- 药理动力学和药理计量学
- 计算生物学 计算生物学
- 药物开发 药物开发
背景情况:
- 敏感性分析对于生理学基础的药理动力学 (PBPK) 模型开发和监管提交至关重要.
- 这些分析评估参数不确定性和可变性,协助模型优化,并测试PBPK模型假设.
研究的目的:
- 介绍一个软件包,用于在开放系统药理学 (OSP) 套件中对PBPK模型进行一次性 (OAT) 和全球敏感性分析 (GSA).
- 为评估参数不确定性对PBPK模型输出和药物相互作用研究的影响提供一个工具.
主要方法:
- 该软件包支持OAT和GSA方法,包括双向局部灵敏度分析,概率不确定性分析,莫里斯,索博尔和EFAST方法.
- 通过R脚本或图形用户界面访问,该工具分析来自OSP套件的PBPK模型.
- 它可以评估药理动力学 (PK) 参数 (例如,Cmax,AUC) 和药理动力学参数比率的敏感度指标,用于药物相互作用研究.
主要成果:
- 该包提供了PK参数的灵敏度指标,与模型输入参数相关.
- 输出格式是为了满足PBPK提交的监管标准.
- 通过三个案例研究证明了实际应用.
结论:
- 开发的软件包为PBPK模型提供了全面的灵敏度分析 (OAT和GSA).
- 该工具支持模型优化,监管合规以及药物相互作用的评估.
- 它提供了一个用户友好的方法来理解PBPK建模中的参数影响.
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