预测系统性和肝脏博森坦暴露使用生理学基础的药理动力学建模
Miao-Chan Huang1, Julia Macente1, Sofie Heylen1
1Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
CPT: pharmacometrics & systems pharmacology
|August 5, 2025
概括
一种新的生理学基础的药理动力学 (PBPK) 模型预测肝脏暴露于博森坦,有助于评估肺动脉高血压患者的风险. 这种模型有助于弥合体外和体内数据,以更好地了解波森坦诱导的肝损伤.
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
- 生物医学工程 生物医学工程
背景情况:
- 博森坦是一种用于肺动脉高血压 (PAH) 的口服药物,具有肝损伤风险的黑盒警告.
- 了解博森坦的肝损伤机制对于准确的风险评估至关重要.
- 将机械学数据与肝脏森坦度相结合,可以提高风险评估.
研究的目的:
- 开发一种基于生理学的药理动力学 (PBPK) 模型,以预测博森坦的肝部位和肝内暴露.
- 为了使森坦诱导的肝损伤的风险评估更加动态和相关.
主要方法:
- 设计了PBPK模型开发的工作流程,重点关注博森坦的肝部位.
- 利用临床血和分泌数据来完善肝脏清除量的估计.
- 与观察到的系统和排泄数据对比验证的模型预测.
主要成果:
- 该PBPK模型准确地预测了博森坦的全身循环和分泌.
- 模型衍生的内在肝清除与临床研究结果一致.
- 模拟的稳定状态未结合的肝脏森坦暴露在1.65至34.1 ng/mL之间.
- 模拟未结合的肝脏与血度的比率在0.80和2.93.9之间变化.
结论:
- 成功开发了一种博森坦PBPK模型,准确预测肝脏的处置.
- 该模型可以预测肝脏的博森坦暴露,将体外毒理学发现与体内效应联系起来.
- 该工具有助于更全面地评估森坦诱导的肝损伤的风险.
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