This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of tegoprazan and to predict the drug–drug interaction (DDI) potential between tegoprazan and cytochrome P450 (CYP) 3A4 perpetrators. The PBPK model of tegoprazan was developed using SimCYP Simulator^® and verified by comparing the model-predicted pharmacokinetics (PKs) of tegoprazan with the observed data from phase 1 clinical studies, including DDI studies. DDIs between tegoprazan and three CYP3A4 perpetrators were predicted by simulating the difference in tegoprazan exposure with and without perpetrators, after multiple dosing for a clinically used dose range. The final PBPK model adequately predicted the biphasic distribution profiles of tegoprazan and DDI between tegoprazan and clarithromycin. All ratios of the predicted-to-observed PK parameters were between 0.5 and 2.0. In DDI simulation, systemic exposure to tegoprazan was expected to increase about threefold when co-administered with the maximum recommended dose of clarithromycin or ketoconazole. Meanwhile, tegoprazan exposure was expected to decrease to ~30% when rifampicin was co-administered. Based on the simulation by the PBPK model, it is suggested that the DDI potential be considered when tegoprazan is used with CYP3A4 perpetrator, as the acid suppression effect of tegoprazan is known to be associated with systemic exposure.

中文翻译：

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使用基于生理学的药代动力学建模和模拟预测替戈拉赞的药物相互作用潜力

本研究旨在开发基于生理学的 tegoprazan 药代动力学 (PBPK) 模型，并预测 tegoprazan 与细胞色素 P450 (CYP) 3A4 肇事者之间的药物相互作用 (DDI) 潜力。替戈拉赞的 PBPK 模型是使用 SimCYP Simulator ^®开发的并通过将替戈拉赞的模型预测药代动力学 (PK) 与 1 期临床研究（包括 DDI 研究）的观察数据进行比较来验证。在临床使用的剂量范围内多次给药后，通过模拟有和没有犯罪者的替戈拉赞暴露差异来预测替戈拉赞和三个 CYP3A4 犯罪者之间的 DDI。最终的 PBPK 模型充分预测了 tegoprazan 和 DDI 在 tegoprazan 和克拉霉素之间的双相分布特征。预测到观察到的 PK 参数的所有比率都在 0.5 和 2.0 之间。在 DDI 模拟中，当与最大推荐剂量的克拉霉素或酮康唑共同给药时，替戈拉赞的全身暴露预计会增加约三倍。同时，当与利福平共同给药时，预计替戈拉赞的暴露量会减少到约 30%。基于 PBPK 模型的模拟，建议将 tegoprazan 与 CYP3A4 肇事者一起使用时考虑 DDI 潜力，因为已知 tegoprazan 的酸抑制作用与全身暴露有关。