血度依赖的结合:通过基于生理学的药物动力学建模来评估TACROLIMUS的影响
Eman El-Khateeb1,2,3, Deeyen Karsanji4,5, Adam S Darwich4,6
1Centre for Applied Pharmacokinetic Research (CAPKR), University of Manchester, Manchester, UK. eman.el-khateeb@certara.com.
Journal of pharmacokinetics and pharmacodynamics
|September 4, 2025
概括
基于生理学的药物动力学模型显示,忽视度依赖的药物与红细胞的结合,可以显著改变药物暴露的预测,特别是对于未结合的药物度.
科学领域:
- 药理动力学和药物代谢
- 基于生理学的药理动力学 (PBPK) 建模
- 药物与红细胞的相互作用
背景情况:
- 药物与红细胞的结合取决于度,使药物动力学评估复杂化.
- 了解血红素等因素如何影响药物行为对于准确的剂量至关重要.
研究的目的:
- 使用生理学基础的药物动力学 (PBPK) 模型,比较度依赖和独立的血度 (B/P).
- 根据不同的约束性假设,评估血红素和剂量对塔克罗利木斯药理学的影响.
主要方法:
- 开发并验证了两种PBPK模型:一种具有和血液结合性,另一种具有恒定的B/ P.
- 模拟的静脉注射和口服用药情景在各种血红素和剂量水平.
- 预测药物度 (总和未结合) 和曲线下的面积 (AUC) 的评估差异.
主要成果:
- 静脉输注中血红素的变化 (15- 45%) 预测了全血AUC的6 - 9%的差异,但未结合的血AUC的差异为37 - 39%.
- 根据具有约束力的假设,口服剂量显示出低度 (50- 130%),高度 (78- 284%) 和AUC (高达125%) 的实质差异.
- 较高的剂量和血红素水平扩大了两种模型之间的差异.
结论:
- 忽视度依赖结合的PBPK模型可能需要补偿参数调整,从而限制预测准确度.
- 准确预测未结合药物度和临床结果需要考虑和红细胞结合.
- 在PBPK模型中选择约束性假设对药物暴露和变异性的预测有重大影响.
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