Abstract
The aim of this review is to assess the effect of genetic factors on the pharmacokinetic parameters of new oral anticoagulants. The review presents data from studies investigating the effect of gene polymorphisms that encode biotransformation enzymes and transporter proteins of new oral anticoagulants on the pharmacokinetics of these drugs. RE-LY study showed a 15% decrease in trough dabigatran concentration and 27% lower risk of bleeding in carriers of CES1 gene rs2244613 polymorphism, there was also a tendency to reduce the risk of major bleeding. Further study of CES1 gene rs8192935 polymorphism showed a 3% decrease in trough dabigatran concentration in heterozygotes and 11% in homozygotes. There was found a 2% and 3% decrease in trough concentrations in hetero- and homozygotes for the minor allele of CES1 gene rs2244613 polymorphism, respectively. There was no significant effect of ABCB1 gene rs2032582 and rs1045642 polymorphisms on dabigatran pharmacokinetics. It is known the case of gastrointestinal bleeding in the carrier of allelic variants of ABCB1 gene rs2032582 and rs1045642 polymorphisms. However, there was no significant effect of genotype on rivaroxaban pharmacokinetics in the study involving the carriers of ABCB1 gene rs2032582 and rs1045642 polymorphisms. ABCB1 gene rs4148738 polymorphism was associated with higher apixaban peak concentration. But groups of patients with acute cardioembolic stroke showed no statistically significant difference of apixaban peak concentration depending on ABCB1 gene rs1045642 polymorphism genotype. ABCB1 gene rs1045642 and SLCO1B1 gene rs4149056 polymorphisms have no effect on edoxaban pharmacokinetics. Elevation of edoxaban metabolite concentration in carriers of SLCO1B1 gene allelic variants was not clinically significant because the proportion of metabolite is about 10% of the concentration of the main substance. It is necessary to provide large population studies with control of treatment efficacy and safety to prove clinical significance of genotyping for new oral anticoagulants use.
Highlights
The aim of this review is to assess the effect of genetic factors on the pharmacokinetic parameters of new oral anticoagulants
RE-LY study showed a 15% decrease in trough dabigatran concentration and 27% lower risk of bleeding in carriers of CES1 gene rs2244613 polymorphism, there was a tendency to reduce the risk of major bleeding
There was no significant effect of ATP binding cassette gene B1 (ABCB1) gene rs2032582 and rs1045642 polymorphisms on dabigatran pharmacokinetics
Summary
Александр Валерьевич Крюков1*, Дмитрий Алексеевич Сычев, Олеся Викторовна Терещенко. В обзоре представлены данные исследований, изучающих влияние полиморфизмов генов, которые кодируют ферменты биотрансформации и белки-переносчики новых оральных антикоагулянтов, на фармакокинетику препаратов данной группы. В исследовании RE-LY у носителей полиморфизма rs2244613 гена CES1 наблюдалось снижение остаточной равновесной концентрации дабигатрана в крови на 15%, и снижение относительного риска развития кровотечений на 27%, а также отмечена тенденция к снижению риска «больших» кровотечений. Последующее исследование полиморфизма rs8192935 гена CES1 показало снижение остаточной равновесной концентрации дабигатрана на 3% у гетерозигот, у гомозигот – на 11%. Однако в исследовании с участием носителей полиморфизмов rs2032582 и rs1045642 гена ABCB1 не наблюдалось существенного влияния генотипа на фармакокинетику ривароксабана. There was no significant effect of genotype on rivaroxaban pharmacokinetics in the study involving the carriers of ABCB1 gene rs2032582 and rs1045642 polymorphisms. For citation: Kryukov A.V., Sychev D.A., Tereshchenko O.V. Pharmacogenetic Aspects of New Oral Anticoagulants Application. По полиморфизму rs8192935 43 пациента имели генотип CC (46,7%; 95% ДИ: 36,9-56,9), 40 пациентов – генотип CT (43,5%; 95% ДИ: 33,8-53,7) и 9 пациентов – генотип TT (9,8%; 95% ДИ: 5,0-17,8)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call