A Physiologically-Based Pharmacokinetic Model for the Prediction of Monoclonal Antibody Pharmacokinetics From In Vitro Data
A Physiologically-Based Pharmacokinetic Model for the Prediction of Monoclonal Antibody Pharmacokinetics From In Vitro Data
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DOI：
10.1002/psp4.12461
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发表时间：
2019-10-01
影响因子：
3.5
通讯作者：
Webster, Robert
中科院分区：
文献类型：
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作者：
Jones, Hannah M.;Zhang, Zhiwei;Webster, Robert
单克隆抗体（mAb）药代动力学（PK）主要通过异速生长比例进行预测，很少考虑新生儿Fc受体（FcRn）亲和力或清除/分布机制的跨种属差异。为了解决这一问题，我们开发了一种基于mAb生理学的PK模型，该模型描述了mAb在人FcRn转基因纯合小鼠和人中的细胞内运输和FcRn再循环。该模型使用mAb特异性体外数据以及物种特异性FcRn组织表达、组织体积和血流生理学来先验预测mAb体内线性PK。该模型在两倍误差内准确预测了90%研究mAb的终末半衰期。该模型的机制性质使我们不仅可以根据体外数据预测线性PK，还可以探索设计成与其靶点或FcRn具有pH依赖性结合的mAb的PK和靶点结合，并且可以帮助选择具有最佳PK和药效学特性的mAb。
Monoclonal antibody (mAb) pharmacokinetics (PK) have largely been predicted via allometric scaling with little consideration for cross-species differences in neonatal Fc receptor (FcRn) affinity or clearance/distribution mechanisms. To address this, we developed a mAb physiologically-based PK model that describes the intracellular trafficking and FcRn recycling of mAbs in a human FcRn transgenic homozygous mouse and human. This model uses mAb-specific in vitro data together with species-specific FcRn tissue expression, tissue volume, and blood-flow physiology to predict mAb in vivo linear PK a priori. The model accurately predicts the terminal half-life of 90% of the mAbs investigated within a twofold error. The mechanistic nature of this model allows us to not only predict linear PK from in vitro data but also explore the PK and target binding of mAbs engineered to have pH-dependent binding to its target or FcRn and could aid in the selection of mAbs with optimal PK and pharmacodynamic properties.