Department of Pharmaceutical Sciences, University at Buffalo, the State University of New York, 452 Kapoor Hall, Buffalo, New York 14260, USA.
AAPS J. 2012 Dec;14(4):850-9. doi: 10.1208/s12248-012-9395-9. Epub 2012 Sep 7.
Efforts have been made to extend the biological half-life of monoclonal antibody drugs (mAbs) by increasing the affinity of mAb-neonatal Fc receptor (FcRn) binding; however, mixed results have been reported. One possible reason for a poor correlation between the equilibrium affinity of mAb-FcRn binding and mAb systemic pharmacokinetics is that the timecourse of endosomal transit is too brief to allow binding to reach equilibrium. In the present work, a new physiologically based pharmacokinetic (PBPK) model has been developed to approximate the pH and time-dependent endosomal trafficking of immunoglobulin G (IgG). In this model, a catenary sub-model was utilized to describe the endosomal transit of IgG and the time dependencies in IgG-FcRn association and dissociation. The model performs as well as a previously published PBPK model, with assumed equilibrium kinetics of mAb-FcRn binding, in capturing the disposition profile of murine mAb from wild-type and FcRn knockout mice (catenary vs. equilibrium model: r (2), 0.971 vs. 0.978; median prediction error, 3.38% vs. 3.79%). Compared to the PBPK model with equilibrium binding, the present catenary PBPK model predicts much more moderate changes in half-life with altered FcRn binding. For example, for a 10-fold increase in binding affinity, the catenary model predicts <2.5-fold change in half-life compared to an ∼8-fold increase as predicted by the equilibrium model; for a 100-fold increase in binding affinity, the catenary model predicts ∼7-fold change in half-life compared to >70-fold increase as predicted by the equilibrium model. Predictions of the new catenary PBPK model are more consistent with experimental results in the published literature.
人们努力通过提高单抗-新生 Fc 受体（FcRn）结合亲和力来延长单克隆抗体药物（mAbs）的生物半衰期；然而，报道的结果却不尽相同。mAb-FcRn 结合的平衡亲和力与 mAb 系统药代动力学之间相关性较差的一个可能原因是内体转运的时间过程过于短暂，无法使结合达到平衡。在本研究中，开发了一种新的基于生理学的药代动力学（PBPK）模型来近似 IgG 的 pH 和时间依赖性内体转运。在该模型中，利用链式子模型来描述 IgG 的内体转运以及 IgG-FcRn 结合和解离的时间依赖性。该模型与假设 mAb-FcRn 结合的平衡动力学的先前发表的 PBPK 模型表现一样好，能够捕获野生型和 FcRn 敲除小鼠中鼠源 mAb 的处置特征（链式与平衡模型：r²，0.971 与 0.978；中位数预测误差，3.38%与 3.79%）。与具有平衡结合的 PBPK 模型相比，当前的链式 PBPK 模型预测 FcRn 结合改变时半衰期的变化要温和得多。例如，对于结合亲和力增加 10 倍，链式模型预测半衰期的变化<2.5 倍，而平衡模型预测的半衰期变化约为 8 倍；对于结合亲和力增加 100 倍，链式模型预测半衰期的变化约为 7 倍，而平衡模型预测的半衰期变化>70 倍。新的链式 PBPK 模型的预测结果与已发表文献中的实验结果更为一致。
