Mu Guangyan, Liu Yaou, Xie Qiufen, Liu Zhiyan, Zhang Hanxu, Meng Xianmin, Song Jinfang, Wang Zhe, Zhou Shuang, Wang Zining, Hu Kun, Zhao Xia, Liao Maoxing, Bao Jiachun, Xiang Qian, Cui Yimin
Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China.
Department of Pharmacy, Peking University First Hospital, Beijing, China.
Curr Pharm Des. 2025;31(9):716-729. doi: 10.2174/0113816128306062241007053405.
To improve the understanding of pharmacokinetic/pharmacodynamic (PK/PD) profiles of apixaban, supporting personalised drug prescriptions for future patients.
Genetic as well as nongenetic factors can affect the predictable PK and PD characteristics of apixaban.
Establish a integrated popPK/PD model that adjusts for critical genetic variant.
The integrated PK/PD models was characterized on the basis of PK (apixaban blood concentration) and PD (prothrombin time (PT), activated partial thromboplastin time (APTT), and anti-FXa activity) data from 181 healthy Chinese volunteers. Other investigated covariate variables included: Meaningful intrinsic and extraneous determinants, correlated genetic factors (ABCG2, F13A1, C3, etc.). A total of 2877 PK concentration observations were included in the modeling dataset.
The PK model of apixaban is adopted by single compartment model with first-order oral absorption. The estimated values of total clearance rate (CL/F), apparent distribution volume (V/F), and absorption rate constant (KA) in the final model are 3.37 L/h, 28.2 L, and 0.781 1/h, respectively. The PK model includes significance covariates such as FOOD, RBC, WT, and gene (ABCG2). The PD model of apixaban is adopted by a linear direct effect model with additive error, which was used to describe the relationship between markers such as APTT, PT, anti-FXa, plasma concentration. PK simulation within the modelled dose range is similar to clinical real date, while PD simulation results also show that the simulated exposure parameters is within the range of the literature.
We established a comprehensive PK/PD model and used it to simulate markers level such as APTT, PT, and anti-FXa of apixaban. Individual predictive values with a dose of 2.5 mg are basically within the expected recommended range.
提高对阿哌沙班药代动力学/药效学（PK/PD）特征的理解，为未来患者的个性化药物处方提供支持。
遗传因素和非遗传因素均可影响阿哌沙班可预测的PK和PD特征。
建立一个针对关键基因变异进行调整的综合群体PK/PD模型。
基于181名健康中国志愿者的PK（阿哌沙班血药浓度）和PD（凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）和抗FXa活性）数据对综合PK/PD模型进行表征。其他研究的协变量变量包括：有意义的内在和外在决定因素、相关遗传因素（ABCG2、F13A1、C3等）。建模数据集中共纳入2877个PK浓度观测值。
阿哌沙班的PK模型采用具有一级口服吸收的单室模型。最终模型中总清除率（CL/F）、表观分布容积（V/F）和吸收速率常数（KA）的估计值分别为3.37 L/h、28.2 L和0.781 1/h。PK模型包括如食物、红细胞、体重和基因（ABCG2）等显著协变量。阿哌沙班的PD模型采用具有加性误差的线性直接效应模型，用于描述APTT、PT、抗FXa等标志物与血浆浓度之间的关系。在模拟剂量范围内的PK模拟与临床实际数据相似，而PD模拟结果也表明模拟的暴露参数在文献报道范围内。
我们建立了一个综合的PK/PD模型，并用于模拟阿哌沙班的APTT、PT和抗FXa等标志物水平。2.5 mg剂量的个体预测值基本在预期推荐范围内。
