用简单和透度有限的生理学基础的药理动力学框架预测清除:对精确炼,分散和并行管肝脏模型进行比较
Swati Nagar1, Rachel Parise2, Ken Korzekwa1
1Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania korzekwa@temple.edu swati.nagar@temple.edu.
概括
预测肝细胞的药物清除是具有挑战性的. 平行管模型通常表现比或分散模型更好,但结合复杂的过程并没有改善预测.
科学领域:
- 药理动力学 药理动力学
- 药物新陈代谢 药物新陈代谢
- 生物制药科学 生物制药科学
背景情况:
- 准确预测肝脏药物清除率对于药物开发至关重要.
- 现有的模型往往难以准确预测清除,特别是在某些药物类别.
- 基于生理学的药理动力学 (PBPK) 框架为建模药物处置提供了更具机制性的方法.
研究的目的:
- 评估各种肝脏模型,包括单间 (1C),透性有限,熟 (WSM),平行管 (PTM) 和分散 (DM) 模型,用于预测肝脏清除.
- 评估诸如间歇液体 (ISF) 蛋白质结合和pH分区等因素对清除预测的影响.
- 为了比较显微体与肝细胞以及不同PBPK模型在预测体外与体内相关性 (IVIVC) 中的性能.
主要方法:
- 使用1C和透性限制模型来评估微小细胞和肝细胞内在清除.
- 在肝脏和全身PBPK框架内评估WSM,PTM和DM模型.
- 研究了ISF蛋白结合的缩放因子对预测准确性的影响,特别是对于酸性化合物.
主要成果:
- 通过WSM和PTM的线性组合,可以准确地估计DM的血度.
- 流量/透度有限的模型显示了酸的系统性误差,通过缩小ISF蛋白结合来减少.
- PTM模型的表现普遍优于WSM和DM模型,显微体和肝细胞之间没有显著差异.
结论:
- PTM模型对预测肝脏清除具有前景,其表现优于其他常用的模型.
- 调整间歇性流体蛋白质结合可以改善酸性药物的预测.
- 尽管纳入了复杂的因素,但当前的模型仍然面临着难以准确预测肝制剂药物清除的挑战.
相关概念视频
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