Sepp Armin, Meno-Tetang Guy, Weber Andrew, Sanderson Andrew, Schon Oliver, Berges Alienor
Systems Modeling and Translational Biology, 1F307 Glaxo Medicines Research Centre, GlaxoSmithKline, Stevenage, SG1 2NY, UK.
Clinical Pharmacology, Modelling and Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, UB11 1BT, UK.
J Pharmacokinet Pharmacodyn. 2019 Aug;46(4):339-359. doi: 10.1007/s10928-019-09640-9. Epub 2019 May 11.
Two-pore physiologically-based pharmacokinetic (PBPK) models can be expected to describe the tissue distribution and elimination kinetics of soluble proteins, endogenous or dosed, as function of their size. In this work, we amalgamated our previous two-pore PBPK model for an inert domain antibody (dAb) in mice with the cross-species platform PBPK model for monoclonal antibodies described in literature into a unified two-pore platform that describes protein modalities of different sizes and includes neonatal Fc receptor (FcRn) mediated recycling. This unified PBPK model was parametrized for organ-specific lymph flow rates and the endosomal recycling rate constant using an extended tissue distribution time-course dataset that included an inert dAb, albumin and IgG in rats and mice. The model was evaluated by comparing the ab initio predictions for the tissue distribution and elimination properties of albumin-binding dAbs (AlbudAbs) in mice and rats with the experimental observations. Due to the large number of molecular species and reactions involved in large-scale PBPK models, we have also developed and deployed a Matlab script for automating the assembly of SimBiology-based two-pore biologics PBPK models which drastically cuts the time and effort required for model building.
基于生理的双孔药代动力学（PBPK）模型有望根据可溶性蛋白质（内源性或给药的）大小来描述其组织分布和消除动力学。在这项工作中，我们将之前针对小鼠体内惰性结构域抗体（dAb）的双孔PBPK模型与文献中描述的单克隆抗体跨物种平台PBPK模型合并为一个统一的双孔平台，该平台可描述不同大小的蛋白质形式，并包括新生儿Fc受体（FcRn）介导的循环利用。利用一个扩展的组织分布时程数据集（其中包括大鼠和小鼠体内的惰性dAb、白蛋白和IgG），针对器官特异性淋巴流速和内体循环速率常数对这个统一的PBPK模型进行了参数化。通过将小鼠和大鼠体内白蛋白结合dAb（AlbudAbs）的组织分布和消除特性的从头预测结果与实验观察结果进行比较，对该模型进行了评估。由于大规模PBPK模型涉及大量分子种类和反应，我们还开发并部署了一个Matlab脚本，用于自动组装基于SimBiology的双孔生物制剂PBPK模型，这大大减少了模型构建所需的时间和精力。
