Park Seongwon, Song Sun-Sook, Jung Woojin, Yun Hwi-Yeol, Lee Soyoung, Kang Sun-Woong, Chae Jung-Woo
College of Pharmacy, Chungnam National University, 99, Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea.
Center for Biomimetic Research, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea.
Comput Struct Biotechnol J. 2025 May 26;27:2424-2433. doi: 10.1016/j.csbj.2025.05.036. eCollection 2025.
This study proposes a novel - extrapolation (IVIVE) strategy that integrates a patented biomimetic system with pharmacokinetic modeling to improve the prediction of drug kinetics. The system employed a single-well plate design with various sizes of mesh inserts to simultaneously assess drug diffusion and cellular metabolism. Drug diffusion patterns were quantified and modeled using a Weibull distribution to establish mathematical relationships between pore size and kinetic parameters. The model was extended to predict the metabolic phase with two drugs, the metabolic conversion of diclofenac into 4-hydroxydiclofenac and metabolic clearance of testosterone in HepaRG cells. The predicted hepatic clearance values derived from the model were consistent with those reported , validating the approach. This integrated strategy enhances IVIVE accuracy and supports the 3 R (replacement, reduction, and refinement) principle by reducing the reliance on animal testing. The findings demonstrate the potential of combining biomimetic systems and mathematical modeling as a reliable platform for pharmacokinetic prediction in drug development.
本研究提出了一种新型的体外体内外推法（IVIVE）策略，该策略将专利仿生系统与药代动力学建模相结合，以改进药物动力学预测。该系统采用单孔板设计，带有各种尺寸的筛网插入物，以同时评估药物扩散和细胞代谢。使用威布尔分布对药物扩散模式进行量化和建模，以建立孔径与动力学参数之间的数学关系。该模型扩展到预测两种药物的代谢阶段，即双氯芬酸向4-羟基双氯芬酸的代谢转化以及HepaRG细胞中睾酮的代谢清除。该模型预测的肝脏清除率值与报道的值一致，验证了该方法。这种综合策略提高了IVIVE的准确性，并通过减少对动物试验的依赖来支持3R（替代、减少和优化）原则。研究结果证明了将仿生系统与数学建模相结合作为药物开发中药代动力学预测可靠平台的潜力。
