Wu Di, Tsekouras Athanasios A, Macheras Panos, Kesisoglou Filippos
Pharmaceutical Sciences and Clinical Supply, Merck & Co., Inc., Rahway, NJ, 07065, USA.
Department of Chemistry, Laboratory of Physical Chemistry, National and Kapodistrian University of Athens, Athens, Greece.
Pharm Res. 2023 Feb;40(2):419-429. doi: 10.1007/s11095-022-03357-0. Epub 2022 Sep 1.
To date, mechanistic modeling of oral drug absorption has been achieved via the use of physiologically based pharmacokinetic (PBPK) modeling, and more specifically, physiologically based biopharmaceutics model (PBBM). The concept of finite absorption time (FAT) has been developed recently and the application of the relevant physiologically based finite time pharmacokinetic (PBFTPK) models to experimental data provides explicit evidence that drug absorption terminates at a specific time point. In this manuscript, we explored how PBBM and PBFTPK models compare when applied to the same dataset. A set of six compounds with clinical data from immediate-release formulation were selected. Both models resulted in absorption time estimates within the small intestinal transit time, with PBFTPK models generally providing shorter time estimates. A clear relationship between the absorption rate and the product of permeability and luminal concentration was observed, in concurrence with the fundamental assumptions of PBFTPK models. We propose that future research on the synergy between the two modeling approaches can lead to both improvements in the initial parameterization of PBPK/PBBM models but to also expand mechanistic oral absorption concepts to more traditional pharmacometrics applications.
迄今为止，口服药物吸收的机制建模是通过使用基于生理学的药代动力学（PBPK）建模，更具体地说是基于生理学的生物药剂学模型（PBBM）来实现的。有限吸收时间（FAT）的概念最近已被提出，相关的基于生理学的有限时间药代动力学（PBFTPK）模型在实验数据中的应用提供了明确的证据，表明药物吸收在特定时间点终止。在本手稿中，我们探讨了将PBBM和PBFTPK模型应用于同一数据集时的比较情况。选择了一组有速释制剂临床数据的六种化合物。两种模型得出的吸收时间估计值均在小肠转运时间范围内，PBFTPK模型通常提供更短的时间估计值。观察到吸收速率与渗透率和管腔浓度乘积之间存在明确关系，这与PBFTPK模型的基本假设一致。我们建议，未来对这两种建模方法协同作用的研究不仅可以改进PBPK/PBBM模型的初始参数化，还可以将机制性口服吸收概念扩展到更传统的药物计量学应用中。
