基于生理学的转化性药理动力学建模,以预测肺部分娩后人类肺部动力学
Haini Wen1, Muhammad Waqas Sadiq2, Lena E Friberg1
1Department of Pharmacy, Uppsala University, Uppsala, Sweden.
为老鼠和人类开发基于生理学上的药理动力学 (PBPK) 模型,可以更好地预测吸入药物的肺部药物暴露,帮助药物开发和安全性评估.
科学领域:
- 药理学 药理学是指药理学的学科.
- 药理动力学 药理动力学
- 药物开发 药物开发
背景情况:
- 从临床前数据来预测人类肺部药物暴露是很困难的.
- 基于生理学的药理动力学 (PBPK) 建模可以弥合翻译差距.
- 吸入药物处置需要一个肺部PBPK框架.
研究的目的:
- 为大鼠开发和验证一种机械性肺PBPK模型.
- 为了使肺药理学从老鼠到人类的跨物种翻译.
- 预测人类肺部对口服吸入药物的药物暴露.
主要方法:
- 综合性肺部排放过程:沉积,溶解,粘膜清除和质量转移.
- 在体内与体外相关性中使用,以将明显的透性转换为有效的透性 (Peff).
- 估计的Peff和未结合的组织-血分区系数 (Kp,u,lung) 使用大鼠Salbutamol和fluticasone propionate的PK数据.
主要成果:
- 开发了一种大鼠肺部PBPK模型,并通过更新生理参数将其转化为人类.
- 在大鼠中估计的沙布塔摩尔和流动 propionate 的 Peff 和 Kp,u,lung 值.
- 成功预测了人类上皮层内液度,折叠误差为肺与血比率<2.
结论:
- 拟议的肺部PBPK框架有助于吸入药物的跨物种翻译.
- 这种模型可以预测肺部输送治疗药物的安全性和有效性.
- PBPK方法提高了从临床前研究中预测人类肺部暴露的确定性.
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