The impact of <i>ABCB1</i> and <i>CES1</i> polymorphisms on dabigatran pharmacokinetics and pharmacodynamics in patients with atrial fibrillation

Ji, Qiuyi; Zhang, Chunyu; Xu, Qing; Zi, Wenjie; Li, Xiaoye; Lv, Qianzhou

doi:10.1111/bcp.14646

Cited by 23 publications

(41 citation statements)

References 24 publications

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“…Our results on the ABCG2 c.421C>A SNV are in line with the results of earlier prospective studies on plasma concentration and drug clearance 11,15,40 as well as with a case report 41 . Our results on CES1 c.257+885T>C SNV are in line with studies reporting association of the variant with drug plasma concentration 13,16,42 …”

Section: Discussionsupporting

confidence: 91%

“…41 Our results on CES1 c.257+885T>C SNV are in line with studies reporting association of the variant with drug plasma concentration. 13,16,42 The present study revealed once again the important role of antiplatelets as interacting drugs. Antiplatelets are in many cases used in parallel with a DOAC to increase protection towards thromboembolic events.…”

Section: Discussionsupporting

confidence: 58%

“…The effect of genetic factors on the pharmacokinetics of DOACs have been investigated in several studies 7–9 . Indications of association between genotypes and drug plasma levels have been found in some studies, 10–17 but also contradictory findings have been reported 5,18,19 …”

mentioning

confidence: 99%

“…5,6 The effect of genetic factors on the pharmacokinetics of DOACs have been investigated in several studies. [7][8][9] Indications of association between genotypes and drug plasma levels have been found in some studies, [10][11][12][13][14][15][16][17] but also contradictory findings have been reported. 5,18,19 In particular, the genome-wide association substudy of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial 13,20 shows associations of ABCB1 and CES1 variants with dabigatran plasma concentration and an association of one CES1 variant with risk of bleeding.…”

mentioning

confidence: 99%

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Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

Lähteenmäki

Vuorinen

Pajula

et al. 2021

Clin Pharma and Therapeutics

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This study aimed to analyze associations between genetic variants and the occurrence of clinical outcomes in dabigatran, apixaban, and rivaroxaban users. This was a retrospective real-world study linking genotype data of three Finnish biobanks with national register data on drug dispensations and healthcare encounters. We investigated several single-nucleotide variants (SNVs) in the ABCG2, ABCB1, CES1, and CYP3A5 genes potentially associated with bleeding or thromboembolic events in direct oral anticoagulant (DOAC) users based on earlier research. We used Cox regression models to compare the incidence of clinical outcomes between carriers and noncarriers of the SNVs or haplotypes. In total, 1,806 patients on apixaban, dabigatran, or rivaroxaban were studied. The ABCB1 c.3435C>T (p.Ile1145=, rs1045642) SNV (hazard ratio (HR) 0.42, 95% confidence interval (CI), 0.18-0.98, P = 0.044) and 1236T-2677T-3435T (rs1128503-rs2032582-rs1045642) haplotype (HR 0.44, 95% CI, 0.20-0.95, P = 0.036) were associated with a reduced risk for thromboembolic outcomes, and the 1236C-2677G-3435C (HR 2.55, 95% CI, 1.03-6.36, P = 0.044) and 1236T-2677G-3435C (HR 5.88, 95% CI, 2.35-14.72, P < 0.001) haplotypes with an increased risk for thromboembolic outcomes in rivaroxaban users. The ABCB1 c.2482-2236G>A (rs4148738) SNV associated with a lower risk for bleeding events (HR 0.37, 95% CI, 0.16-0.89, P = 0.025) in apixaban users. ABCB1 variants are potential factors affecting thromboembolic events in rivaroxaban users and bleeding events in apixaban users. Studies with larger numbers of patients are warranted for comprehensive assessment of the pharmacogenetic associations of DOACs and their relevance for clinical practice.Direct oral anticoagulants (DOACs) are increasingly used in the context of various clinical conditions and procedures, including atrial fibrillation (ischemic stroke prevention), deep vein thrombosis, and pulmonary embolism. DOACs have favorable pharmacodynamic and pharmacokinetic properties and do not require continuous therapeutic monitoring except in specific

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 58%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

Lähteenmäki

Vuorinen

Pajula

et al. 2021

Clin Pharma and Therapeutics

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“…In addition, the genotype frequency of Chinese in our study is very similar to that of Chinese in other study. 19 In the present study the Cmax and AUC 0-∞ of total dabigatran were approximately 20% higher than that in Caucasians. Allele C of CES1 rs2244613 was associated with decreased dabigatran trough concentration and decreased risk of bleeding, but not to the peak concentration.…”

Section: Discussioncontrasting

confidence: 45%

The Impact of ABCB1 and CES1 Polymorphisms on Dabigatran Pharmacokinetics in Healthy Chinese Subjects

Liu¹,

Yang²,

Wei³

et al. 2021

PGPM

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Dabigatran is a novel direct oral anticoagulant agent, whose plasma concentration is closely related to bleeding risk. Genetic polymorphisms can affect the level of plasma dabigatran. The purpose of this study was to understand the relationship between dabigatranrelated genes and the plasma level of dabigatran in healthy Chinese subjects after taking a single oral dose. This study was performed with a single-center, single-dose, randomized, open-label, and four-period crossover trial design under both fasting and fed conditions. A total of 106 eligible healthy subjects were enrolled in the study and 104 were genotyped. One-way analysis of variance (ANOVA) was used to compare pharmacokinetic parameters among different genotypes and linear regression was applied to explore the multiplicative interaction between variables. In this study, we found that the genotype frequencies of CES1 rs2244613 and CES1 rs8192935 were significantly different between Chinese and Caucasians, but the genotype frequencies of ABCB1 rs1045642 and ABCB1 rs4148738 were similar in both populations. CES1 rs8192935 were associated with the peak concentration of dabigatran. There was no significant gender difference in the exposure level of dabigatran. Furthermore, food significantly delayed the absorption of dabigatran but had little effect on C max and AUC 0-∞ .

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Rationale and design of the optimal antithrombotic treatment for acute coronary syndrome patients with concomitant atrial fibrillation and implanted with new‐generation drug‐eluting stent: OPtimal management of anTIthroMbotic Agents (OPTIMA)‐4 trial

Gong

Hua

Bai

et al. 2023

Clinical Cardiology

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The impact of ABCB1 and CES1 polymorphisms on dabigatran pharmacokinetics and pharmacodynamics in patients with atrial fibrillation

Cited by 23 publications

References 24 publications

Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

The Impact of ABCB1 and CES1 Polymorphisms on Dabigatran Pharmacokinetics in Healthy Chinese Subjects

Rationale and design of the optimal antithrombotic treatment for acute coronary syndrome patients with concomitant atrial fibrillation and implanted with new‐generation drug‐eluting stent: OPtimal management of anTIthroMbotic Agents (OPTIMA)‐4 trial

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