构建沙格列汀PK/PD模型——模拟其在健康人群和肝损伤患者的药动学和药效学

在本次研究中,我们旨在开发和评价沙格列汀的全身生理药代动力学(WB-PBPK)/药效学(PD)模型,模拟其在健康成人及肝功能损害患者中的药代动力学和药效学特性,为特殊患者的临床药学研究提供新方法.基于文献中获取的如logD和血浆蛋白结合率等药物特征参数,建立WB-PBPK模型和PD模型.将模拟所得的血药浓度-时间曲线及...

A PK/PD model of saxagliptin: to simulate its pharmacokinetics and pharmacodynamics in healthy adults and patients with impaired hepatic function

In this study, we aimed to develop and evaluate a whole-body physiologically based pharmacokinetic (WB-PBPK)/pharmacodynamic (PD) model for saxagliptin, simulate its pharmacokinetic and pharmacodynamic properties in healthy adults and patients with hepatic function impairment, and provide a new method for the research to the clinical pharmacy of special patients. Based on the drug-specific properties, such as logD, plasma protein binding collected by the published literature, the WB-PBPK model and the PD model were established. After comparing the simulated concentration-time profiles and the pharmacokinetic parameters with data in healthy adults from oral and intravenous clinical investigation, the WB-PBPK model could be optimized. After comparing the simulated DPP-4 inhibition profile with the observed pharmacodynamic in healthy subjects, the PD model could be optimized. The PK/PD model was utilized to predict the mean and variability of the pharmacokinetic and pharmacodynamic profiles in subjects with different hepatic impairment. All of the predicted pharmacokinetic curves were comparable to the observed curves both in healthy subjects and hepatic impairment subjects (C_max and AUC were less than 1.3-fold). The predicted pharmacodynamic curves were comparable to the observed ones in different oral dosage after optimization, and pharmacodynamics of saxagliptin in hepatic impairment subjects were predicted successfully. The WB-PBPK/PD model can accurately simulate the pharmacokinetics and pharmacodynamics of saxagliptin in normal adults and different hepatic impaired patients.