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

doi:10.5246/jcps.2021.02.010

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (2): 119-132.DOI: 10.5246/jcps.2021.02.010

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

石璐¹^,^#, 苗丰¹^,^#, 汪国鹏², 孙文燕¹^,^*(), 刘洋³^,^*()

1. 北京中医药大学中药学院中药药理系, 北京 102488
2. 中财瀚熙生物科技发展有限公司, 北京 101500
3. 北京中医药大学中药学院中药化学系, 北京 102488

收稿日期:2020-11-10 修回日期:2020-11-24 接受日期:2020-12-08 出版日期:2021-02-28 发布日期:2021-02-27
通讯作者: 孙文燕, 刘洋
作者简介:
+ Tel.: +86-13520838769, E-mail: sunwy@bucm.edu.cn
+ Tel.: +86-13810283092, E-mail: liuyang@bucm.edu.cn

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

Lu Shi¹^,^#, Feng Miao¹^,^#, Guopeng Wang², Wenyan Sun¹^,^*(), Yang Liu³^,^*()

1 Department of Pharmacology of Chinese Materia Medica, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
2 Zhongcai Health (Beijing) Biological Technology Development Co., Ltd., Beijing 101500, China
3 Department of Chemistry of Chinese Materia Medica, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China

Received:2020-11-10 Revised:2020-11-24 Accepted:2020-12-08 Online:2021-02-28 Published:2021-02-27
Contact: Wenyan Sun, Yang Liu
About author:
# Lu Shi and Feng Miao contributed equally to this work and should be regarded as co-first authors.

摘要/Abstract

摘要：

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-时间曲线及药代动力学参数与临床研究数据进行比较，优化WB-PBPK模型。将模拟所得的DPP-4抑制曲线与临床药效学数据进行比较, 优化PD模型。该PK/PD模型用于预测不同程度肝损伤患者的药代动力学和药效学特征。模型预测的药代动力学曲线与实测的健康和肝损伤受试者曲线重合度良好(C_max和AUC倍数误差小于1.3倍)。模型预测的药效学曲线与实测值拟合良好, 并成功预测了沙格列汀在肝损伤受试者中的药效学状态。该试验所建立的WB-PBPK/PD模型可较好模拟沙格列汀在正常成人和不同程度肝功能受损患者体内的药代动力学和药效学。

关键词: PK/PD模型构建, 肝损伤, 沙格列汀, GastroPlus

Abstract:

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.

Key words: PK/PD modeling, Hepatic impairment, Saxagliptin, GastroPlus

Supporting:

石璐, 苗丰, 汪国鹏, 孙文燕, 刘洋. 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[J]. 中国药学(英文版), 2021, 30(2): 119-132.

Lu Shi, Feng Miao, Guopeng Wang, Wenyan Sun, Yang Liu. A PK/PD model of saxagliptin: to simulate its pharmacokinetics and pharmacodynamics in healthy adults and patients with impaired hepatic function[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(2): 119-132.

图/表 23

Figure 1. Schematic structure of the whole-body PBPK model used to predict in vivo behaviors of saxagliptin in different human populations. The blood flow rates associated with the 14 compartments-lung (Lu), liver (Li), spleen (Sp), gut (AC), adipose (Ad), muscle (Mu), heart (He), brain (Br), kidney (Ki), skin (Sk), reproductive organ (RO), red marrow (RM), yellow marrow (YM), rest of body (ROB), are represented by Q, subscripted with the corresponding compartment. Qha is the blood flow rate to the liver via hepatic artery (ha).

Table 1. The mean physiological parameters used in the WB-PBPK absorption models.

Table 2. Physicochemical properties and in vitro data used in the simulations.

Figure 2. Simulated (line) and observed (points) plasma concentration-time profiles after 40 μg intravenous administration in healthy subjects (29 years old, western).

Table 3. Predicted and observed parameters of saxagliptin after intravenous administration in healthy adults.

Table 4. Predicted and observed parameters of saxagliptin after 5 mg oral administration in healthy adults.

Figure 3. Simulated (line) and observed (points) plasma concentration-time profiles after 5 mg administration in healthy subjects (42 years old, western).

Figure 4. Simulated (line) and observed (points) plasma concentration-time profiles after 2.5 mg administration in healthy subjects (29 years old, western).

Figure 5. Simulated (line) and observed (points) plasma concentration-time profiles after 50 mg administration in healthy subjects (29 years old, western).

Table 5. Observed and predicted pharmacokinetic parameters of saxagliptin after oral administration in healthy adults.

Figure 6. Simulated (line) and observed (points) plasma concentration-time curve in patients with mild hepatic impairment after 10 mg oral administration (52 years old, western).

Figure 7. Simulated (line) and observed (points) plasma concentration-time curve in patients with moderate hepatic impairment after 10 mg oral administration (52 years old, western).

Figure 8. Simulated (line) and observed (points) plasma concentration-time curve in patients with severe hepatic impairment after 10 mg oral administration (51 years old, western).

Table 6. Observed and predicted pharmacokinetic parameters of saxagliptin between different patients with hepatic impairment after oral 10 mg administration.

Table 7. Pharmacokinetic parameters of healthy subjects and patients with hepatic impairment after oral 10 mg administration.

Table 8. The fitting data of all the models.

Figure 9. Simulated (lines) and observed (points) pharmacokinetic and pharmacodynamic profile after 5 mg oral administration in healthy subjects (42 years old, western).

Table 9. The fitting parameters after optimized.

Figure 10. Simulate (lines) and observed (points) pharmacokinetic and pharmacodynamic profile after 2.5, 5 50 mg oral administration in healthy adults (42 and 29 years old, western) before optimized.

Figure 11. Simulate (lines) and observed (points) pharmacokinetic and pharmacodynamic profile after 2.5, 5, 50 mg oral administration in healthy adults (42 and 29 years old, western) after optimization.

Figure 12. Simulated PBPK/PD profile with 10 mg oral administration in mild hepatic impairment patients.

Figure 13. Simulated PBPK/PD profile with 10 mg oral administration in moderate hepatic impairment patients.

Figure 14. Simulated PBPK/PD profile with 10 mg oral administration in severe hepatic impairment patients.

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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

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

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