Effect of CYP3A4 Inhibitors and Inducers on Pharmacokinetics and Pharmacodynamics of Saxagliptin and Active Metabolite M2 in Humans Using Physiological-Based Pharmacokinetic Combined DPP-4 Occupancy

沙沙利汀 药代动力学 药理学 CYP3A4型 化学 药效学 生物利用度 最大值 CYP3A型 药物相互作用 代谢物 医学 CYP2D6型 曲线下面积 口服 交叉研究 体内 活性代谢物 基于生理学的药代动力学模型 酮康唑 药品 肠促胰岛素 细胞色素P450 内科学 二甲双胍 生物化学 新陈代谢 磷酸西他列汀 胰岛素
作者
Gang Li,Bowen Yi,Jingtong Liu,Xiaoquan Jiang,Fulu Pan,Wenning Yang,Haibo Li,Yang Liu,Guopeng Wang
出处
期刊:Frontiers in Pharmacology [Frontiers Media]
卷期号:12 被引量:7
标识
DOI:10.3389/fphar.2021.746594
摘要

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.
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