与阿哌沙班在中国健康志愿者体内药代动力学和药效学相关的遗传生物标志物的鉴定。

IF 3.9 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Expert Opinion on Drug Metabolism & Toxicology Pub Date : 2023-01-01 DOI:10.1080/17425255.2023.2184344

Guangyan Mu, Qiufen Xie, Zhiyan Liu, Hanxu Zhang, Xianmin Meng, Jinfang Song, Shuang Zhou, Zhe Wang, Zining Wang, Xia Zhao, Jie Jiang, Maoxing Liao, Jiachun Bao, Fan Zhang, Qian Xiang, Yimin Cui

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引用次数: 0

摘要

背景:阿哌沙班是一种优越的直接口服抗凝剂，在现实世界中，其浓度和反应在个体间存在差异。本研究旨在确定与阿哌沙班在中国健康受试者体内药代动力学(PK)和药效学(PD)相关的遗传生物标志物。方法:本多中心研究纳入181名健康中国成人，单剂量服用2.5 mg或5mg阿哌沙班，并评估其PK和PD参数。采用Affymetrix Axiom CBC_PMRA阵列进行全基因组单核苷酸多态性(SNP)基因分型。通过候选基因关联分析和全基因组关联研究，鉴定对阿哌沙班的PK和PD参数具有预测价值的基因。结果:几种ABCG2变异与阿哌沙班的Cmax和AUC0-t相关(p -5)，不同ABCG2基因型的抗xa3h活性和dPT3h也存在显著差异(p发现ABLIM2变异与阿哌沙班的PK特性相关，F13A1和C3变异与阿哌沙班的PD特性相关(p -8)。结论:ABCG2变异体是阿哌沙班PK和PD特征的理想遗传生物标志物。ABLIM2、F13A1和C3被确定为与阿哌沙班个体间变异相关的潜在候选基因。该研究已在ClinicalTrials.gov注册，编号NCT03259399。

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Identification of genetic biomarkers associated with pharmacokinetics and pharmacodynamics of apixaban in Chinese healthy volunteers.

Background: Apixaban is a superior direct oral anticoagulant exihibiting interindividual variability in concentration and response in the real world. The present study aimed to identify genetic biomarkers associated with pharmacokinetics (PK) and pharmacodynamics (PD) of apixaban in healthy Chinese subjects.

Methods: This multicenter study included 181 healthy Chinese adults taking a single dose of 2.5 mg or 5 mg apixaban and assessed their PK and PD parameters. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed using the Affymetrix Axiom CBC_PMRA Array. Candidate gene association analysis and genome-wide association study were conducted to identify genes with a predictive value for PK and PD parameters of apixaban.

Results: Several ABCG2 variants were associated with C_max and AUC_0-t of apixaban (p < 6.12 × 10^-5) and also presented significant differences of anti-Xa_3h activity and dPT_3h according to different ABCG2 genotypes (p < 0.05). Besides, ABLIM2 variants were found to be associated with PK characteristics and F13A1 and C3 variants were associated with PD characteristics of apixaban (p < 9.46 × 10^-8).

Conclusion: ABCG2 variants were found to be ideal genetic biomarkers for both PK and PD characteristics of apixaban. ABLIM2, F13A1 and C3 were identified as potential candidate genes associated with inter-individual variability of apixaban. This study was registered on ClinicalTrials.gov NCT03259399.

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来源期刊

Expert Opinion on Drug Metabolism & Toxicology 医学-生化与分子生物学

CiteScore

7.90

自引率

2.30%

发文量

审稿时长

4-8 weeks

期刊介绍： Expert Opinion on Drug Metabolism & Toxicology (ISSN 1742-5255 [print], 1744-7607 [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles on all aspects of ADME-Tox. Each article is structured to incorporate the author’s own expert opinion on the scope for future development. The Editors welcome: Reviews covering metabolic, pharmacokinetic and toxicological issues relating to specific drugs, drug-drug interactions, drug classes or their use in specific populations; issues relating to enzymes involved in the metabolism, disposition and excretion of drugs; techniques involved in the study of drug metabolism and toxicology; novel technologies for obtaining ADME-Tox data. Drug Evaluations reviewing the clinical, toxicological and pharmacokinetic data on a particular drug. The audience consists of scientists and managers in the pharmaceutical industry, pharmacologists, clinical toxicologists and related professionals.