Wiśniowska Barbara, Giebułtowicz Joanna, Piotrowski Roman, Kułakowski Piotr, Polak Sebastian
Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
Department of Bioanalysis and Drugs Analysis, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland.
Pharmaceuticals (Basel). 2022 Mar 20;15(3):379. doi: 10.3390/ph15030379.
Antazoline is an antihistaminic drug that is effective in the termination of paroxysmal atrial fibrillation. Despite its long presence in the market, antazoline's ADME parameters and pharmacokinetic effects in humans are poorly characterized. The objective of this study was to fill this gap by generation of in vitro and in vivo data and the development of a physiologically based pharmacokinetic model describing antazoline and its main metabolite disposition. A set of ADME parameters for the antazoline and its hydroxy metabolite is provided based on literature data, QSAR predictions, in vitro binding and metabolic stability assays. These can be used to feed PBPK models. In our current work, the developed PBPK model simulating simultaneously the pharmacokinetic profile of antazoline and its metabolite was successfully verified against the available clinical data and the presented capability to account for the clinically observed variability. When used to feed the PD model (e.g., simulating ECG), concentration-time profiles predicted by the model enable the assessment of antazoline's effect in various clinical scenarios with the possibility to account for population differences or CP mediated drug-drug interactions.
安他唑啉是一种抗组胺药，对终止阵发性心房颤动有效。尽管安他唑啉已在市场上存在很长时间，但其在人体中的药代动力学参数和药代动力学效应仍未得到充分表征。本研究的目的是通过生成体外和体内数据以及开发描述安他唑啉及其主要代谢产物处置的基于生理的药代动力学模型来填补这一空白。基于文献数据、定量构效关系预测、体外结合和代谢稳定性试验，提供了一组安他唑啉及其羟基代谢产物的药代动力学参数。这些参数可用于构建生理药代动力学模型。在我们目前的工作中，所开发的同时模拟安他唑啉及其代谢产物药代动力学特征的生理药代动力学模型已成功地根据现有临床数据进行了验证，并展示了其解释临床观察到的变异性的能力。当用于构建药效学模型（例如模拟心电图）时，该模型预测的浓度-时间曲线能够评估安他唑啉在各种临床情况下的效果，并有可能考虑人群差异或细胞色素P450介导的药物相互作用。
