Dabigatran pharmacogenetics and secondary prevention of ischemic stroke
Authors:
A. Olšerová; P. Janský; T. Šrámková; A. Tomek
Authors‘ workplace:
Neurologická klinika 2. LF UK a FN Motol, Praha
Published in:
Cesk Slov Neurol N 2022; 85(4): 281-286
Category:
Review Article
doi:
https://doi.org/10.48095/cccsnn2022281
Overview
Due to its proven safety and efficacy, the direct anticoagulant dabigatran is often the first choice in the secondary prevention of cardioembolic stroke in atrial fibrillation. The recommended dosage of 110 and 150 mg twice daily creates a variation in plasma levels within the therapeutic range in the treatment population. The inter-individual variability of these levels may be caused by polymorphisms of genes involved in drug transport and metabolism. Although the pharmacogenetic examination of some gene polymorphisms in the selection of drugs is currently implemented in routine clinical practice, the use of the genetic profile of patients treated with dabigatran in order to increase the safety of anticoagulant therapy is not yet part of the recommended procedures. We searched for published studies investigating polymorphisms of the CES1 and ABCB1 genes, which are involved in the absorption and metabolism of dabigatran. The most promising for clinical relevance is the rs2244613 polymorphism in the CES1 gene, which is associated with a decrease in dabigatran concentration and a lower risk of bleeding without a simultaneous increased risk of recurrence of ischemia. Carriers of the rs2244613 variant may significantly benefit from dabigatran treatment. The pharmacogenetics of dabigatran may be clinically beneficial for safer and more effective secondary prevention of cardioembolic stroke, but further clinical studies are required.
Keywords:
ischemic stroke – SNP – bleeding – personalized medicine – thrombosis – dabigatran – direct oral anticoagulants – Pharmacogenetics – embolism – ABCB1 – CES1
Sources
1. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12): 1139–1151. doi: 10.1056/NEJM- oa0905561.
2. Ferro JM, Coutinho JM, Dentali F et al. RE-SPECT CVS Study Group. Safety and efficacy of dabigatran etexilate vs dose-adjusted warfarin in patients with cerebral venous thrombosis: a randomized clinical trial. JAMA Neurol 2019; 76 (12): 1457–1465. doi: 10.1001/jamaneurol.2019.2764.
3. Wang D, Johnson AD, Papp AC et al. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharm Genom 2005; 15: 693–704. doi: 10.1097/01.fpc.0000178311.02878.83.
4. Durães AR, de Souza Roriz P, de Almeida Nunes B et al. Dabigatran versus warfarin after bioprosthesis valve replacement for the management of atrial fibrillation postoperatively. Drugs R D 2016; 16 (2): 149–154. doi: 10.1007/s40268-016-0124-1.
5. Robinson AA, Trankle CR, Eubanks G et al. Off-label use of direct Oral anticoagulants compared with warfarin for left ventricular thrombi. JAMA Cardiol 2020; 5 (6): 685–692. doi: 10.1001/jamacardio.2020.0652.
6. Pradaxa: summary of product characteristics. [online]. Available from URL: https: //www.ema.europa.eu/en/documents/productinformation/pradaxa-epar-product-information_en.pdf.
7. Paré G, Eriksson N, Lehr T et al. Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation 2013; 127 (13): 1404–1412. doi: 10.1161/CIRCULATIONAHA.112.001233.
8. Chin PK, Wright DF, Zhang M et al. Correlation between trough plasma dabigatran concentrations and estimates of glomerular filtration rate based on creatinine and cystatin C. Drugs in R&D 2014; 14 (2): 113–123. doi: 10.1007/s40268-014-0045-9.
9. Dimatteo C, Andrea G, Vecchione G et al. Pharmacogenetics of dabigatran etexilate interindividual variability. Thromb Res 2016; 144: 1–5. doi: 10.1016/j.thromres.2016.05.025.
10. Shi J, Wang X, Nguyen JH et al. Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender. Biochem Pharmacol 2016; 119: 76–84. doi: 10.1016/j.bcp.2016.09. 003.
11. Gouin-Thibault I, Delavenne X, Blanchard A et al. Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB1 genetic polymorphisms and interaction with clarithromycin. J Thromb Haemost 2017; 15 (2): 273–283. doi: 10.1111/jth.13577.
12. Sychev DA, Levanov AN, Shelekhova TV et al. The impact of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) gene polymorphisms on dabigatran equilibrium peak concentration in patients after total knee arthroplasty. Pharmgenomics Pers Med 2018; 11: 127–137. doi: 10.2147/PGPM.S169277.
13. Tomek A, Olšerová A, Boudníková A et al. The correlation of through plasmatic concentration of dabigatran and CES1 genotype with major bleeding complications in stroke patients [abstract]. Stroke 2018; 49 (Suppl_1): TMP110. doi: 10.1161/str.49.suppl_1.TMP110.
14. Tomek A, Olšerová A, Janský P et al. Predictors of clinically relevant bleeding and overdose in prospectively followed cohort of dabigatran treated stroke patients [abstract]. Eur Stroke J 2018; 3 (1S): 535.
15. Lähteenmäki J, Vuorinen AL, Pajula J et al. Pharmacogenetics of bleeding and thromboembolic events in direct oral anticoagulant users. Clin Pharmacol Ther 2021; 110 (3): 768–776. doi: 10.1002/cpt.2316.
16. Liu Y, Yang C, Qi W et al. The impact of ABCB1 and CES1 polymorphisms on dabigatran pharmacokinetics in healthy chinese subjects. Pharmacogenomics Pers Med 2021; 14: 477–485. doi: 10.2147/PGPM.S291 723.
17. Xie Q, Li Y, Liu Z et al. SLC4A4, FRAS1, and SULT1A1 genetic variations associated with dabigatran metabolism in a healthy chinese population. Front Genet 2022; 13: 873031. doi: 10.3389/fgene.2022.873031.
18. Laizure SC, Parker RB, Herring VL et al. Identification of carboxylesterase-dependent dabigatran etexilate hydrolysis. Drug Metab Dispos 2013; 42 (2): 201–206. doi: 10.1124/dmd.113.054353.
19. Ganetsky M, Babu KM, Salhanick SD et al. Dabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant. J Med Toxicol 2011; 7 (4): 281–287. doi: 10.1007/s13181-011-0178-y.
20. Ishiguro N, Kishimoto W, Volz A et al. Impact of endogenous esterase activity on in vitro p-glycoprotein profiling of dabigatran etexilate in Caco-2 monolayers. Drug Metab Dispos 2014; 42 (2): 250–256. doi: 10.1124/dmd.113.053561.
21. Blech S, Ebner T, Ludwig-Schwellinger E et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36 (2): 386–399. doi: 10.1124/dmd.107.019 083.
22. Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost 2010; 103 (3): 572–585. doi: 10.1160/TH09-09- 0659.
23. Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran ete- xilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 2009; 15 (Suppl 1): 9S–16S. doi: 10.1177/1076029 609343004.
24. Merali Z, Ross S, Paré G. The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect. Drug Metabol Drug Interact 2014; 29 (3): 143–151. doi: 10.1515/dmdi-2014-0009.
25. Bodor M, Kelly EJ, Ho RJ et al. Characterization of the human MDR1 gene. AAPS J 2005; 7 (1): E1–E5. doi: 10.1208/aapsj070101.
26. Clinical pharmacology and biopharmaceutics review of Pradaxa. [online]. Available form URL: https: // www.accessdata.fda.gov/drugsatfda_docs/nda/2010/ 022512Orig1s000ClinPharmR_Corrrected%203.11.2011.pdf.
27. Sherry ST, Ward MH, Kholodov M et al. dbSNP: The NCBI database of genetic variation. Nucleic Acids Res 2001; 29 (1): 308–311. doi: 10.1093/nar/29.1.308.
28. Kim RB, Leake BF, Choo EF. et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 2001; 70 (2): 189–199. doi: 10.1067/mcp.2001.117412.
29. Xie Q, Xiang Q, Mu G et al. Effect of ABCB1 genotypes on the pharmacokinetics and clinical outcomes of new oral anticoagulants: a systematic review and meta-analysis. Curr Pharm Des 2018; 24 (30): 3558–3565. doi: 10.2174/1381612824666181018153641.
30. Reilly PA, Lehr T, Haertter S et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63 (4): 321–328. doi: 10.1016/j.jacc.2013.07.104.
31. Shore S, Carey EP, Turakhia MP et al. Adherence to dabigatran therapy and longitudinal patient outcomes: insights from the veterans health administration. Am Heart J 2014; 167 (6): 810–817. doi: 10.1016/j.ahj.2014. 03.023.
32. Pharmacogenomics Knowledgebase (PharmGKB). [online]. Available from URL: https: //www.pharmgkb.org/chemical/PA165110351/clinicalAnnotation.
33. Kaufman AL, Spitz J, Jacobs M et al. evidence for clinical implementation of pharmacogenomics in cardiac drugs. Mayo Clin Proc 2015; 90 (6): 716–729. doi: 10.1016/j.mayocp.2015.03.016.
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Paediatric neurology Neurosurgery NeurologyArticle was published in
Czech and Slovak Neurology and Neurosurgery
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