Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, BioPharm Building, Room 341, 789 S. Limestone, Lexington, Kentucky, 40536, USA.
Pharm Res. 2018 Feb 6;35(3):47. doi: 10.1007/s11095-017-2292-2.
The aim of this study was to develop a two-pore minimum physiologically-based pharmacokinetic (mPBPK) model in describing the pharmacokinetic (PK) of therapeutic monoclonal antibody (TMAb) in human subjects.
PK data used in this study were endogenous/exogenous native IgG and two TMAbs (palivizumab and Motavizumab-YTE) in normal volunteer or familial hypercatabolic hypoproteinemia (FIHH) patient. Several important components were implemented to overcome the limitations of the early mPBPK model, e.g. two-pore model to describe the transcapillary transport of IgG from vascular to interstitial space. Six mPBPK models with different osmotic reflection coefficient (OFC) of transcapillary transport, endocytosis rates (ETR) and plasma clearance for the TMAbs/IgG were tested and the best model was selected using AICc values.
The final model consisted of different OFC and ETR values for native IgG and TMAbs, supporting the hypothesis that the dynamics in the endosomal space had an important role in the compliant FcRn salvage mechanism to determine the clearance of TMAbs. The estimated FcRn concentration of FIHH subjects was 2.72 μmol/l. The final two-pore mPBPK model has a better performance for native IgG than previously developed mPBPK model.
The final two-pore mPBPK model not only overcome the limitations of the early mPBPK model but also has a better performance to describe the disposition of the IgG antibody in human subjects.
本研究旨在开发一个双孔最小生理基于药代动力学（mPBPK）模型，以描述人受试者中治疗性单克隆抗体（TMAb）的药代动力学（PK）。
本研究中使用的 PK 数据是内源性/外源性天然 IgG 和两种 TMAb（帕利珠单抗和莫替唑单抗-YTE）在正常志愿者或家族性高代谢性低蛋白血症（FIHH）患者中的数据。实施了几个重要的组件来克服早期 mPBPK 模型的局限性，例如双孔模型来描述 IgG 从血管到间质空间的跨毛细血管转运。测试了六个具有不同跨毛细血管转运渗透压反射系数（OFC）、内吞率（ETR）和 TMAb/IgG 血浆清除率的 mPBPK 模型，并使用 AICc 值选择最佳模型。
最终模型由天然 IgG 和 TMAb 的不同 OFC 和 ETR 值组成，支持内体空间动力学在确定 TMAb 清除率的顺应性 FcRn 拯救机制中起重要作用的假设。FIHH 受试者的估计 FcRn 浓度为 2.72 μmol/L。最终的双孔 mPBPK 模型对天然 IgG 的性能优于先前开发的 mPBPK 模型。
最终的双孔 mPBPK 模型不仅克服了早期 mPBPK 模型的局限性，而且对描述人受试者中 IgG 抗体的处置具有更好的性能。
