Algharably Engi Abdelhady, Di Consiglio Emma, Testai Emanuela, Pistollato Francesca, Mielke Hans, Gundert-Remy Ursula
Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Clinical Pharmacology and Toxicology, Berlin, Germany.
Mechanisms, Biomarkers and Models Unit, Environment and Health Department, Istituto Superiore di Sanità, Rome, Italy.
Front Toxicol. 2022 Jul 18;4:885843. doi: 10.3389/ftox.2022.885843. eCollection 2022.
Physiologically based kinetic (PBK) modeling has been increasingly used since the beginning of the 21st century to support dose selection to be used in preclinical and clinical safety studies in the pharmaceutical sector. For chemical safety assessment, the use of PBK has also found interest, however, to a smaller extent, although an internationally agreed document was published already in 2010 (IPCS/WHO), but at that time, PBK modeling was based mostly on data as the example in the IPCS/WHO document indicates. Recently, the OECD has published a guidance document which set standards on how to characterize, validate, and report PBK models for regulatory purposes. In the past few years, we gained experience on using data for performing quantitative - extrapolation (QIVIVE), in which biokinetic data play a crucial role to obtain a realistic estimation of human exposure. In addition, pharmaco-/toxicodynamic aspects have been introduced into the approach. Here, three examples with different drugs/chemicals are described, in which different approaches have been applied. The lessons we learned from the exercise are as follows: 1) conditions should be considered and compared to the situation, particularly for protein binding; 2) inhibition of metabolizing enzymes by the formed metabolites should be taken into consideration; and 3) it is important to extrapolate from the measured intracellular concentration and not from the nominal concentration to the tissue/organ concentration to come up with an appropriate QIVIVE for the relevant adverse effects.
自21世纪初以来，基于生理学的动力学（PBK）模型越来越多地被用于支持制药行业临床前和临床安全性研究中的剂量选择。对于化学安全性评估，PBK的应用也受到了关注，不过程度较小，尽管2010年已发布了一份国际认可的文件（IPCS/WHO），但当时PBK建模大多基于数据，如IPCS/WHO文件中的示例所示。最近，经合组织发布了一份指导文件，为监管目的设定了如何表征、验证和报告PBK模型的标准。在过去几年中，我们在使用数据进行定量外推（QIVIVE）方面积累了经验，其中生物动力学数据对于获得人体暴露的实际估计起着关键作用。此外，药代动力学/毒代动力学方面也已被引入该方法。这里描述了三个使用不同药物/化学品的例子，其中应用了不同的方法。我们从这些实例中学到的经验教训如下：1）应考虑条件并与情况进行比较，特别是对于蛋白质结合；2）应考虑形成的代谢物对代谢酶的抑制作用；3）从测量的细胞内浓度而非标称浓度外推到组织/器官浓度以得出针对相关不良反应的合适QIVIVE非常重要。
