Li Gang, Yi Bowen, Liu Jingtong, Jiang Xiaoquan, Pan Fulu, Yang Wenning, Liu Haibo, Liu Yang, Wang Guopeng
Beijing Adamadle Biotech Co, Ltd., Beijing, China.
Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Front Pharmacol. 2021 Oct 19;12:746594. doi: 10.3389/fphar.2021.746594. eCollection 2021.
We aimed to develop a physiological-based pharmacokinetic and dipepidyl peptidase 4 (DPP-4) occupancy model (PBPK-DO) characterized by two simultaneous simulations to predict pharmacokinetic (PK) and pharmacodynamic changes of saxagliptin and metabolite M2 in humans when coadministered with CYP3A4 inhibitors or inducers. Ketoconazole, delavirdine, and rifampicin were selected as a CYP3A4 competitive inhibitor, a time-dependent inhibitor, and an inducer, respectively. Here, we have successfully simulated PK profiles and DPP-4 occupancy profiles of saxagliptin in humans using the PBPK-DO model. Additionally, under the circumstance of actually measured values, predicted results were good and in line with observations, and all fold errors were below 2. The prediction results demonstrated that the oral dose of saxagliptin should be reduced to 2.5 mg when coadministrated with ketoconazole. The predictions also showed that although PK profiles of saxagliptin showed significant changes with delavirdine (AUC 1.5-fold increase) or rifampicin (AUC: a decrease to 0.19-fold) compared to those without inhibitors or inducers, occupancies of DPP-4 by saxagliptin were nearly unchanged, that is, the administration dose of saxagliptin need not adjust when there is coadministration with delavirdine or rifampicin.
我们旨在开发一种基于生理学的药代动力学和二肽基肽酶4（DPP-4）占有率模型（PBPK-DO），该模型通过两个同步模拟来表征，以预测与CYP3A4抑制剂或诱导剂合用时，沙格列汀及其代谢物M2在人体内的药代动力学（PK）和药效学变化。分别选择酮康唑、地拉韦啶和利福平作为CYP3A4竞争性抑制剂、时间依赖性抑制剂和诱导剂。在此，我们使用PBPK-DO模型成功模拟了沙格列汀在人体内的PK曲线和DPP-4占有率曲线。此外，在实际测量值的情况下，预测结果良好且与观察结果一致，所有倍数误差均低于2。预测结果表明，与酮康唑合用时，沙格列汀的口服剂量应减至2.5mg。预测还显示，尽管与无抑制剂或诱导剂时相比，沙格列汀的PK曲线与地拉韦啶（AUC增加1.5倍）或利福平（AUC：降至0.19倍）合用时显示出显著变化，但沙格列汀对DPP-4的占有率几乎不变，即与地拉韦啶或利福平合用时，沙格列汀的给药剂量无需调整。
