rpcardioRational Pharmacotherapy in CardiologyРациональная Фармакотерапия в Кардиологии1819-64462225-3653«SILICEA-POLIGRAF» LLC10.20996/1819-6446-2023-2970DZRUERrpcardio-2970Research ArticleORIGINAL STUDIESОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯPharmacogenetics and pharmacokinetics of rivaroxaban in patients with atrial fibrillation and chronic kidney diseaseФармакогенетика и фармакокинетика ривароксабана у пациентов с фибрилляцией предсердий и хронической болезнью почекhttps://orcid.org/0000-0001-6823-6077ШаталоваН. А.ShatalovaN. A.

Шаталова Наталья Андреевна - ассистент, кафедра терапии и полиморбидной патологии имени академика М.С. Вовси.

Москва

Natalya A. Shatalova - Assistant of Therapy and Polymorbid Pathology named after Academician M.S. Vovsi Dept.

Moscow

shatalova_23-1994@mail.ruhttps://orcid.org/0000-0002-4496-3680СычевД. А.SychevD. A.

Сычев Дмитрий Алексеевич – доктор медицинских наук, профессор, академик РАН, ректор, заведующий кафедрой клинической фармакологии и терапии имени академика Б.Е. Вотчала.

Москва

Dmitriy A. Sychev - MD, PhD, Professor, head of the Department of Clinical Pharmacology and Therapy named after Academician B.E. Votchal Russian Medical Academy of Continuing Professional Education of the Ministry of Healthcare of the Russian Federation.

Moscow

dmitry.alex.sychev@gmail.comhttps://orcid.org/0000-0002-9307-4994МирзаевК. Б.MirzaevK. B.

Мирзаев Карин Бадавиевич - доктор медицинских наук, проректор по научной работе и инновациям, директор НИИ молекулярной и персонализированной медицины, профессор кафедры клинической фармакологии и терапии имени академика Б.Е. Вотчала.

Москва

Karin B. Mirzaev - MD, PhD, Vice-Rector for Research and Innovation, Director of Research Institute of Molecular and Personalized Medicine, Professor of the Department of Clinical Pharmacology and Therapy named after Academician B.E. Votchal, Russian Medical Academy of Continuing Professional Education of the Ministry of Healthcare of the Russian Federation.

Moscow

karin05doc@yandex.ruhttps://orcid.org/0000-0001-5801-3742КочетковА. И.KochetkovA. I.

Кочетков Алексей Иванович – кандидат медицинских наук, доцент кафедры терапии и полиморбидной патологии имени академик М.С. Вовси.

Москва

Alexey I. Kochetkov - MD, PhD, Associate Professor of the Department of Therapy and Polymorbid Pathology Department named after Academician M.S. Vovsi, Russian Medical Academy of Continuing Professional Education of the Ministry of Healthcare of the Russian Federation.

Moscow

ak_info@list.ruhttps://orcid.org/0000-0001-6573-4169ЭбзееваЕ. Ю.EbzeevaE. Yu.

Эбзеева Елизавета Юрьевна - кандидат медицинских наук, доцент кафедры терапии и полиморбидной патологии имени академика М.С. Вовси.

Москва

Elizaveta Yu. Ebzeeva - MD, PhD, Associate Professor of the Department  of Therapy and Polymorbid Pathology Department named after Academician M.S. Vovsi, Russian Medical Academy of Continuing Professional Education of the Ministry of Healthcare of the Russian Federation.

Moscow

veta-veta67@mail.ruhttps://orcid.org/0000-0002-8926-6731ДашабыловаВ. Б.DashabylovaV. B.

Дашабылова Виктория Баторовна - ординатор 1-го года обучения кафедры терапии и полиморбидной патологии имени академика М.С. Вовси.

Москва

Victoria B. Dashabylova - 2st year medical residentof the Department  of Therapy and Polymorbid Pathology Department named after Academician M.S. Vovsi, Russian Medical Academy of Continuing Professional Education of the Ministry of Healthcare of the Russian Federation.

Moscow

dash.victoriya@yandex.ruhttps://orcid.org/0000-0001-8555-5969БочковП. О.BochkovP. O.

Бочков Павел Олегович – кандидат биологических наук, старший научный сотрудник отдела предиктивных и прогностических биомаркеров научно-исследовательского института молекулярной и персонализированной медицины.

Москва

Pavel O. Bochkov - Senior Researcher, Department of Predictive and Prognostic Biomarkers of the Research Institute of Molecular and Personalized Medicine, Russian Medical Academy of Continuous Professional Education.

Moscow

bok-of@yandex.ruhttps://orcid.org/0009-0001-2744-2752ТучковаС. Н.TuchkovaS. N.

Тучкова Светлана Николаевна - младший научный сотрудник отдела предиктивных и прогностических биомаркеров научно-исследовательского института молекулярной и персонализированной медицины.

Москва

Svetlana N. Tuchkova - junior researcher, Department of Predictive and Prognostic Biomarkers of the Research Institute of Molecular and Personalized Medicine, Russian Medical Academy of Continuous Professional Education.

Moscow

svetlanatuch1998@gmail.comhttps://orcid.org/0009-0008-9053-6779ГлаголевС. В.GlagolevS. V.

Глаголев Сергей Владимирович.

Москва

Sergey V. Glagolev.

Moscow

Российская медицинская академия непрерывного профессионального образования Минздрава РоссииРоссияRussian Medical Academy of Continuous Professional EducationRussian FederationМинистерство здравоохранения Российской ФедерацииРоссияMinistry of Health of the Russian FederationRussian Federation202307112023195470478Copyright © Shatalova N.A., Sychev D.A., Mirzaev K.B., Kochetkov A.I., Ebzeeva E.Y., Dashabylova V.B., Bochkov P.O., Tuchkova S.N., Glagolev S.V., 20232023Шаталова Н.А., Сычев Д.А., Мирзаев К.Б., Кочетков А.И., Эбзеева Е.Ю., Дашабылова В.Б., Бочков П.О., Тучкова С.Н., Глаголев С.В.Shatalova N.A., Sychev D.A., Mirzaev K.B., Kochetkov A.I., Ebzeeva E.Y., Dashabylova V.B., Bochkov P.O., Tuchkova S.N., Glagolev S.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.rpcardio.online/jour/article/view/2970Aim

Aim. To study the possible relationship between polymorphic variants of ABCB1 (rs2032582, rs1045642, rs1128503), CYP3A5 (rs776746), CYP3A4 (rs35599367) and CYP2J2 (rs890293) genes with residual equilibrium concentrations (Cmin,ss) of rivaroxaban in patients with non-valvular atrial fibrillation (AF) and stage 3 and 4 chronic kidney disease (CKD).

Material and methods

Material and methods. A total of 123 patients 52 to 97 years old (median age, 82 years) with AF in combination with stage 3 and 4 CKD were included in the study. Each patient underwent a pharmacogenetic and pharmacokinetic study.

Results

Results. Cmin,ss and dose-adjusted concentration (Cmin,ss/D) of rivaroxaban were significantly higher in patients with the TT genotype than with the CT genotype of the polymorphic variant rs1045642 of the ABCB1 gene (Сmin,ss 60,5 [36,7;173] ng/ml and 54,8 [23,1;97,3] ng/ml, respectively, р=0,016; Сmin,ss/D 4,06[2,3;8,1] ng/ml/mg and 2,2 [1,1;4,9] ng/ml/mg, р=0,006). In patients with the T allele (CT and TT genotypes), compared with CC genotype carriers, Cmin,ss and Cmin,ss/D were significantly higher (Cmin,ss 60,5 [36,7;173] ng/ml and 45,8 [20,9;82,3] ng/ml, respectively, p=0,029; Cmin,ss/D 4,06 [2,3;8,1] ng/ml/  mg and 2,6 [1,2;4,8] ng/ml/mg, respectively, p=0,014). Also, Cmin,ss and Cmin,ss/D was significantly higher in patients with the TT genotype according to the polymorphic variant rs2032582 of the ABCB1 gene than in patients with the GG genotype (p=0,02 and р=0,016 respectively). Cmin,ss and Cmin,ss/D in T allele (GT and TT genotypes) carriers were significantly higher than in T allele homozygotes (Cmin,ss 57,1 [27,7;106,0] ng/ml versus 37,6 [18,6;61,7] ng/ml respectively, p=0,024; Cmin,ss/D 3,6 [1,7;7,4] ng/ml/mg versus 2,3 [1,1;4,09] ng/ml/mg respectively, p=0,032). Differences in Сmin,ss and Сmin,ss/D of rivaroxaban were detected when comparing TC, CC and TT genotypes of polymorphism rs1128503 of the ABCB1 gene. When comparing Сmin,ss and Сmin,ss/D of rivaroxaban among carriers of AG and GG genotypes of the rs776746 polymorphism of the CYP3A56986A>G gene, no significance was detected (p>0,05). Also, no difference in Cmin,ss and Cmin,ss/D was found when comparing carriers of the CC and CT genotypes of the rs35599367 polymorphism of the CYP3A4 gene, and carriers of the CC and AC genotypes of the rs890293 polymorphism of the CYP2J2 gene (p>0,05).

Conclusion

Conclusion. The carriage of T allele by polymorphic variants rs1045642 and rs2032582 of the ABCB1 gene affects Cmin,ss and Cmin,ss/D of rivaroxaban.

Цель

Цель. Изучить взаимосвязь между наличием полиморфных вариантов генов ABCB1 (rs2032582, rs1045642, rs1128503), CYP3A5 (rs776746), CYP3A4 (rs35599367) и CУP2J2 (rs890293) и остаточной равновесной концентрацией (Сmin,ss) ривароксабана у пациентов с неклапанной фибрилляцией предсердий (ФП) и хронической болезнью почек (ХБП) 3 и 4 стадий.

Материал и методы

Материал и методы. В исследование включены123 пациента в возрасте от 52 до 97 лет (медиана возраста 82 года) с ФП в сочетании с ХБП 3 и 4 стадий. Выполнены фармакокинетическое и фармакогенетическое тестирования.

Результаты

Результаты. Сmin,ss и остаточная концентрация, скорректированная по дозе (Сmin,ss/D) ривароксабана были статистически значимо выше у пациентов с генотипом ТТ, чем с генотипом СТ по полиморфному варианту rs 1045642 гена ABCB1 (Сmin,ss 60,5 [36,7;173] нг/мл и 54,8 [23,1;97,3] нг/мл, соответственно, р=0,016; Сmin,ss/D 4,06 [2,3;8,1] нг/мл/мг и 2,2 [1,1;4,9] нг/мл/мг, соответственно, р=0,006). У пациентов, имеющих Т аллель (генотипы СТ и ТТ), по сравнению с носителями генотипа СС, Сmin,ss и Сmin,ss/D были статистически значимо выше (Сmin,ss 60,5 [36,7;173] нг/мл и 45,8 [20,9;82,3] нг/мл, соответственно, р=0,029; Сmin,ss/D 4,06 [2,3;8,1] нг/мл/мг и 2,6 [1,2;4,8] нг/мл/мг, соответственно, р=0,014). Также Сmin,ss и Сmin,ss/D были статистически значимо выше у пациентов с генотипом ТТ по полиморфному варианту rs2032582 гена ABCB1, чем у пациентов с генотипом GG (р=0,02 и р=0,016, соответственно). Сmin,ss и Сmin,ss/D у носителей аллеля Т (генотипы GT и ТТ) были статистически значимо выше, чем у гомозигот по аллелю Т (Сmin,ss 57,1 [27,7;106,0] нг/мл против 37,6 [18,6;61,7] нг/мл, соответственно, р=0,024; Сmin,ss/D 3,6[1,7;7,4] нг/мл/мг против 2,3 [1,1;4,09] нг/мл/мг, соответственно, р=0,032). Не было выявлено разницы Сmin,ss и Сmin,ss/D ривароксабана при сравнении генотипов TC, CC и ТТ полиморфизма rs1128503 гена ABCB1. При сравнении Сmin,ss и Сmin,ss/D ривароксабана среди носителей генотипов AG и GG полиморфизма rs776746 гена CYP3A56986A>G не было выявлено статистической значимости (p>0,05). Также не обнаружено разницы Сmin,ss и Сmin,ss/D при сравнении носистелей генотипов CC и CТ полиморфизма rs35599367 гена CYP3A4, и носителей СС и АС полиморфизма rs890293 гена CYP2J2 (p>0,05).

Заключение

Заключение. Носительство аллелей Т по полиморфным вариантам rs1045642 и rs2032582 гена ABCB1 влияет на Сmin,ss и Сmin,ss/D ривароксабана.

фибрилляция предсердийхроническая болезнь почекривароксабанфармакокинетикафармакогенетикаatrial fibrillationchronic kidney diseaserivaroxabanpharmacokineticspharmacogeneticsИсследование выполнено при поддержке грантом РНФ № 22–15–00251 "Персонализированное применение прямых оральных антикоагулянтов на основе фармакогеномного подхода".The study was performed with the support of Russian Science Foundation, project no. 22-15-00251 "Personalized use of direct oral anticoagulants based on the pharmacogenomic approach".ReferencesVirani SS, Alonso A, Benjamin EJ, et al. Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation. 2020;141(9):139-596. DOI:10.1161/CIR.0000000000000757.Virani SS, Alonso A, Benjamin EJ, et al. 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The authors declare that there are no conflicts of interest present.