基于模型的稳定状态药理动力学预测使用高通量带输液方法在小鼠中
Saivishal Daripelli1,2, Amol Achyutrao Raje1, Vishwottam Kandikere1
1Drug Metabolism and Pharmacokinetics, Discovery Biology, Syngene International Limited, Bangalore-560099 India.
这项研究在小鼠中使用磁带剂量来预测Fulvestrant,Imipramine和Brivaracetam的稳定状态药物度. 药理动力学建模方法成功指导了用于早期药物发现的剂量预测.
科学领域:
- 药理学 药理学是指药理学的学科.
- 药物代谢和药理动力学
- 临床前药物开发 临床前药物开发
背景情况:
- 达到稳定状态药物度对于临床前暴露-反应评估至关重要.
- 磁带剂量允许同时对多种化合物的药理动力学评估.
研究的目的:
- 使用磁带剂量评估富尔韦斯特兰特,伊米普拉和布里瓦拉塞坦的药理动力学 (PK).
- 在小鼠中建模输液速率以达到目标稳定状态度 (Css).
- 通过卡塞特输液验证基于模型的剂量预测.
主要方法:
- 在体外肝脏稳定性测试 (微小体,肝细胞) 评估药物相互作用.
- 在CD-1小鼠中单剂量皮下 (SC) PK研究.
- 分区建模用于预测PK参数和输注速率.
- 用Alzet的奥斯莫斯进行168小时的SC卡塞特输液,用于验证.
主要成果:
- 没有观察到显著的体外药物相互作用.
- 布里瓦拉塞坦呈现出高暴露率和低清除率; 伊米普拉胺显示出快速消除.
- 分区建模准确预测了输液剂量,尽管观察到的Css低于预测.
- 所有化合物在24-36小时内达到稳定状态,清除/暴露排名一致.
结论:
- 结合SC PK概况,建模和磁带输注的综合方法使得有效的基于模型的剂量预测成为可能.
- 这种方法支持药物发现中的早期PK评估和配方开发.
- 该研究证明了磁带剂量和建模对于预测稳定状态药物度的有用性.
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