ABSTRACT

Two-pore physiologically-based pharmacokinetics (PBPK) for biologics describes the tissue distribution and elimination kinetics of soluble proteins as a function of their hydrodynamic radius and the physiological properties of the organs. Whilst many studies have been performed in rodents to parameterize the PBPK framework in terms of organ-specific lymph flow rates, similar validation in humans has been limited. This is mainly due to the paucity of the tissue distribution time course data for biologics that is not distorted by target-related binding. Here, we demonstrate that a PBPK model based on rodent data provided good to satisfactory extrapolation to the tissue distribution time course of ⁸⁹Zr-labeled albumin-binding domain antibody (AlbudAb™) GSK3128349 in healthy human volunteers, including correct prediction of albumin-like plasma half-life, volume of distribution, and extravasation half-life. The AlbudAb™ used only binds albumin, and hence it also provides information about the tissue distribution kinetics and turnover of that ubiquitous and multifunctional plasma protein.

摘要

生物制剂的双孔基于生理学的药代动力学 (PBPK) 描述了可溶性蛋白质的组织分布和消除动力学，作为其流体动力学半径和器官生理特性的函数。虽然已经在啮齿动物中进行了许多研究，以根据器官特异性淋巴流速来参数化 PBPK 框架，但在人类中的类似验证受到限制。这主要是由于生物制剂的组织分布时程数据缺乏不会被靶标相关结合扭曲。在这里，我们证明了基于啮齿动物数据的 PBPK 模型对⁸⁹Zr 标记的白蛋白结合域抗体 (AlbudAb™) GSK3128349 在健康人类志愿者中的应用，包括对白蛋白样血浆半衰期、分布容积和外渗半衰期的正确预测。所用的 AlbudAb™ 仅结合白蛋白，因此它还提供有关该无处不在的多功能血浆蛋白的组织分布动力学和周转的信息。