Yang Zhuan, Tan Wen Rui, Li Qin, Wang Ying, Liu Shijing, Chen Lu, Zhou Yan, Zeng Chen, Zeng Yan, Xiong Yun, Zhang Qian, Li Na, Du Peng, Liu Lin, Chen Jiyu, He Yan
Clinical Trials Center, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
School of Pharmacy, Guizhou Medical University, Guiyang, China.
Front Pharmacol. 2024 Nov 15;15:1454612. doi: 10.3389/fphar.2024.1454612. eCollection 2024.
The impact of genetic polymorphisms in the ABCB1 and CES1 genes on dabigatran plasma concentrations remains a subject of debate, and the purpose of this study was to quantitatively assess the effects of genetic polymorphisms on dabigatran esters in healthy Chinese subjects employed a population pharmacokinetic (PopPK) approach.
In total, 1,926 pharmacokinetic (PK) samples from 123 healthy individuals who were given 150 mg of dabigatran orally during a fasting state or postprandially were analyzed using the PopPK model. A two-compartment model with first-order absorption was found to adequately describe the PK data.
The results showed that covariates food intake and ABCB1 SNP rs4148738 were shown to have statistically significant impacts. Specifically, in postprandial administration increased lag time (ALAG) and clearance (CL) by 2.65% and 0.51%, respectively, and decreased absorption rate constant (KA) by 0.24%. Additionally, in subjects with CT genotype ABCB1 (rs4148738), the central ventricular volume of distribution (V) was increased by 0.38%.
In summary, the PopPK model developed in this study was robust and effectively characterized the pharmacokinetics of dabigatran in healthy Chinese adults, demonstrating that both food and ABCB1 genetic variation significantly influence the absorption and plasma concentration levels of dabigatran.
ABCB1和CES1基因的遗传多态性对达比加群血浆浓度的影响仍是一个有争议的话题，本研究的目的是采用群体药代动力学（PopPK）方法定量评估健康中国受试者中遗传多态性对达比加群酯的影响。
总共对123名健康个体在禁食状态或餐后口服150mg达比加群后获得的1926份药代动力学（PK）样本，使用PopPK模型进行分析。发现具有一级吸收的二室模型能够充分描述PK数据。
结果表明，协变量食物摄入和ABCB1单核苷酸多态性rs4148738具有统计学上的显著影响。具体而言，餐后给药分别使滞后时间（ALAG）和清除率（CL）增加2.65%和0.51%，使吸收速率常数（KA）降低0.24%。此外，在ABCB1（rs4148738）基因型为CT的受试者中，中央室分布容积（V）增加了0.38%。
总之，本研究开发的PopPK模型稳健，有效地表征了达比加群在健康中国成年人中的药代动力学，表明食物和ABCB1基因变异均显著影响达比加群的吸收和血浆浓度水平。
