Clinical Review of the Pharmacogenomics of Direct Oral Anticoagulants

Tseng, Andrew; Patel, Reema D.; Quist, Heidi E.; Kekic, Adrijana; Maddux, Jacob T.; Grilli, Christopher B; Shamoun, Fadi

doi:10.1007/s10557-018-6774-1

Cited by 18 publications

(15 citation statements)

References 23 publications

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“…The influence of genetic factors on drug responses is complex, and genetic structure differences are thought to be the main factors leading to individual differences (Paré et al, 2013;Dimatteo et al, 2016;Rodríguez-Vicente et al, 2016). Genetic polymorphisms in a series of metabolic enzymes, transporters, receptors, and other drug targets involved in the process of drug delivery in vivo cause individual differences in drug efficacy and toxicity (Klein et al, 2017;Tseng et al, 2018). P-gp is an important transporter for many drugs in vivo (Choo et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Influence of ABCB1 Gene Polymorphism on Rivaroxaban Blood Concentration and Hemorrhagic Events in Patients With Atrial Fibrillation

Wang

Chen

et al. 2021

Front. Pharmacol.

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Background and Objectives: Genetic data on the pharmacokinetics of rivaroxaban and identification of factors that affect its biotransformation, distribution, and excretion will allow for generation of algorithms for personalized use of this drug in patients with atrial fibrillation (AF). Here we tested the effects of ABCB1 (ATP-binding cassette subfamily B member 1) polymorphisms on the valley rivaroxaban blood concentration and on the frequency of hemorrhagic events in patients with AF and propose a personal anticoagulation therapy management protocol.Patients and Methods: This is a retrospective study. We enrolled Mongolian descent patients who met the criteria from May 2018 to August 2019 in Beijing and Fujian. Clinical data on gender, height, weight, liver and kidney functions, drug trough concentration, and drug dosage were collected; we recorded the bleeding events until 6 months after initiating the medication. ABCB1 single nucleotide polymorphisms including rs1128503, rs1045642, and rs4148738 were identified. After reaching the steady state of plasma concentration, the peripheral blood was collected to detect the trough rivaroxaban plasma concentrations before the next medication.Results: We included 155 patients in this study including 81 men and 74 women, with an average age of 71.98 ± 10.72 years. The distribution of ABCB1 genotypes conformed to the Hardy–Weinberg equilibrium. Multiple comparisons between wild (TT) and mutant (CT and CC) genotypes at the rs1045642 locus showed no significant differences of rivaroxaban trough concentrations (TT vs. CT, p = 0.586; TT vs. CC, p = 0.802; and CT vs. CC, p = 0.702). Multiple comparison between wild (TT) and mutant (CC) genotypes at the rs1128503 locus revealed a significant difference of rivaroxaban trough concentrations (TT vs. CC, p = 0.0421). But wild (TT) vs mutant (CT) genotypes and mutant CT vs mutant CC genotypes at the rs1128503 locus showed no significant differences of rivaroxaban trough concentrations (TT vs. CT, p = 0.0651; TT vs. CT, p = 0.6127). Multiple comparisons between wild (GG) and mutant (AG and AA) genotypes at the rs4148738 locus showed no significant differences of rivaroxaban trough concentrations (GG vs. AG, p = 0.341; GG vs. AA, p = 0.612; AG vs. AA, p = 0.649). There was no significant correlation between ABCB1 gene variation loci rs1045642, rs1128503, rs4148738 and bleeding events.Conclusion: rs1128503 locus variations are correlated with the serum concentration of rivaroxaban in patients of Mongolian descent. But no significant correlation between rs1128503 locus variations and bleeding events were obtained.

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Section: Discussionmentioning

confidence: 99%

Influence of ABCB1 Gene Polymorphism on Rivaroxaban Blood Concentration and Hemorrhagic Events in Patients With Atrial Fibrillation

Wang

Chen

et al. 2021

Front. Pharmacol.

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“…Additionally, it was required that the patient’s genetic variant data were available from the biobanks. We analyzed genetic variants which have been identified in earlier research to be potentially associated with bleeding or thromboembolic events in DOAC users 7,8 …”

Section: Methodsmentioning

confidence: 99%

“…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%

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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“…Inter-individual variability in response to pharmacotherapy as well as molecular/physiologic "subtypes" of patients within the broad category of AD support the rationale for a personalized therapeutic approach based on unique genetic characteristics and individual lifestyle attributes (Hahn and Lee, 2019). There is growing interest in the use of pharmacogenomics to optimize the safety and efficacy of DOACs in anticoagulation therapy (Tseng et al, 2018). As more data using this approach become available, incorporating DOACs into a personalized precision medicine approach for the treatment of AD could be accomplished in the near future.…”

Section: Future Directionsmentioning

confidence: 99%

Thrombin, a Mediator of Coagulation, Inflammation, and Neurotoxicity at the Neurovascular Interface: Implications for Alzheimer’s Disease

2020

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The societal burden of Alzheimer's disease (AD) is staggering, with current estimates suggesting that 50 million people worldwide have AD. Identification of new therapeutic targets is a critical barrier to the development of disease-modifying therapies. A large body of data implicates vascular pathology and cardiovascular risk factors in the development of AD, indicating that there are likely shared pathological mediators. Inflammation plays a role in both cardiovascular disease and AD, and recent evidence has implicated elements of the coagulation system in the regulation of inflammation. In particular, the multifunctional serine protease thrombin has been found to act as a mediator of vascular dysfunction and inflammation in both the periphery and the central nervous system. In the periphery, thrombin contributes to the development of cardiovascular disease, including atherosclerosis and diabetes, by inducing endothelial dysfunction and related inflammation. In the brain, thrombin has been found to act on endothelial cells of the blood brain barrier, microglia, astrocytes, and neurons in a manner that promotes vascular dysfunction, inflammation, and neurodegeneration. Thrombin is elevated in the AD brain, and thrombin signaling has been linked to both tau and amyloid beta, pathological hallmarks of the disease. In AD mouse models, inhibiting thrombin preserves cognition and endothelial function and reduces neuroinflammation. Evidence linking atrial fibrillation with AD and dementia indicates that anticoagulant therapy may reduce the risk of dementia, with targeting thrombin shown to be particularly effective. It is time for "outside-the-box" thinking about how vascular risk factors, such as atherosclerosis and diabetes, as well as the coagulation and inflammatory pathways interact to promote increased AD risk. In this review, we present evidence that thrombin is a convergence point for AD risk factors and as such that thrombin-based therapeutics could target multiple points of AD pathology, including neurodegeneration, vascular activation, and neuroinflammation. The urgent need for disease-modifying drugs in AD demands new thinking about disease pathogenesis and an exploration of novel drug targets, we propose that thrombin inhibition is an innovative tactic in the therapeutic battle against this devastating disease.

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Clinical Review of the Pharmacogenomics of Direct Oral Anticoagulants

Cited by 18 publications

References 23 publications

Influence of ABCB1 Gene Polymorphism on Rivaroxaban Blood Concentration and Hemorrhagic Events in Patients With Atrial Fibrillation

Influence of ABCB1 Gene Polymorphism on Rivaroxaban Blood Concentration and Hemorrhagic Events in Patients With Atrial Fibrillation

Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

Thrombin, a Mediator of Coagulation, Inflammation, and Neurotoxicity at the Neurovascular Interface: Implications for Alzheimer’s Disease

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