The impact of ABCB1 and CES1 polymorphisms on dabigatran pharmacokinetics and pharmacodynamics in patients with atrial fibrillation
The impact of ABCB1 and CES1 polymorphisms on dabigatran pharmacokinetics and pharmacodynamics in patients with atrial fibrillation
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DOI：
10.1111/bcp.14646
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发表时间：
2020-12-10
影响因子：
3.4
通讯作者：
Lv, Qianzhou
中科院分区：
文献类型：
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作者：
Ji, Qiuyi;Zhang, Chunyu;Lv, Qianzhou
目的研究ABCB1和CES1基因多态性对达比加群在非瓣膜性心房颤动（NVAF）患者中的药代动力学（PK）和药效学（PD）的影响。方法我们进行了一项前瞻性研究，纳入了使用达比加群治疗的非瓣膜性房颤患者。每位患者采集血样，用于基因分型和测定血浆达比加群浓度（PDC）和凝血参数，包括活化部分凝血活酶时间（APTT）和凝血酶时间。患者的人口统计数据和预定随访的临床结果都被记录下来。统计分析遗传多态性对达比加群患者PK/PD和出血风险的影响。结果共纳入198例患者。ABCB1多态性rs4148738和rs1045642与达比加群PK/PD无显著相关性。对于CES1多态性rs8192935，次要等位基因(C)与低谷PDCs增加相关（方差分析：P < 0.001； CC与TT基因型，P < 0.001； CT与TT基因型，P = 0.014），与低谷APTT值相关（P = 0.015）。对于CES1多态性rs2244613，小等位基因(A)携带者的槽PDC水平高于非携带者（方差分析：P < 0.001； AA与CC基因型，P < 0.001； CA与CC基因型，P = 0.004），小出血风险增加（P = 0.034；优势比= 2.71,95%置信区间1.05-7.00）。结论CES1 SNP rs8192935上的小等位基因C与PDCs和APTT值存在低谷相关。在接受达比加群治疗的非瓣膜性房颤患者中，CES1 SNP rs2244613上的小等位基因(A)与通过PDCs增加和小出血风险增加相关。
Aims Our study aimed to determine the impact of genetic polymorphisms of ABCB1 and CES1 on the pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran in patients with nonvalvular atrial fibrillation (NVAF).Methods We conducted a prospective study and enrolled NVAF patients treated with dabigatran. Blood samples were obtained from each patient and used for genotyping and determination of plasma dabigatran concentration (PDC) and coagulation parameters including activated partial thromboplastin time (APTT) and thrombin time. Patients' demographics and clinical outcomes from scheduled follow-up visits were all recorded. Statistical analysis was performed to identify the impact of genetic polymorphisms on the PK/PD and bleeding risk of dabigatran.Results A total of 198 patients were included in analysis. For the ABCB1 polymorphisms rs4148738 and rs1045642, no significant association was found with dabigatran PK/PD. For the CES1 polymorphism rs8192935, the minor allele(C) was associated with increased trough PDCs (ANOVA: P < .001; CC vs. TT genotype, P < .001; CT vs. TT genotype, P = .014) and with APTT values at trough level (P = .015). For the CES1 polymorphism rs2244613, the minor allele(A) carriers had higher levels of trough PDC than noncarriers (ANOVA: P < .001; AA vs. CC genotype, P < .001; CA vs. CC genotype, P = .004) and increased risk for minor bleeding (P = .034; odds ratio = 2.71, 95% confidence interval 1.05-7.00).Conclusion Our study indicated that the minor allele(C) on the CES1 SNP rs8192935 was associated with PDCs and APTT values at trough level. The minor allele(A) on the CES1 SNP rs2244613 was associated with increased trough PDCs and higher risk for minor bleeding in NVAF patients treated with dabigatran.