medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/ms2023-332medsovet-7814Research ArticleПРАКТИКАPRACTICEАнтикоагулянтная терапия апиксабаном на основе фармакогенетического подхода: курс на безопасностьAnticoagulant therapy with apixaban based on a pharmacogenetic approach: a course to safetyhttps://orcid.org/0000-0002-6417-9535ФединаЛ. В.FedinaL. V.

Федина Людмила Владимировна - аспирант кафедры клинической фармакологии и терапии, Российская медицинская академия непрерывного профессионального образования; врач – клинический фармаколог отделения клинической фармакологии, Городская клиническая больница имени С.С. Юдина.

125993, Москва, ул. Баррикадная, д. 2/1, стр. 1; 115446, Россия, Москва, Коломенский проезд, д. 4

Ludmila V. Fedina - Postgraduate Student of the Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education; Clinical Pharmacologist, Department of Clinical Pharmacology.

2/1, Bldg. 1, Barrikadnaya St., Moscow, 125993; 4, Kolomensky Proezd, Moscow, 115446

fedina201368@gmail.comhttps://orcid.org/0000-0002-2970-3442СычевИ. Н.SychevI. N.

Сычев Игорь Николаевич - кандидат медицинских наук, доцент кафедры клинической фармакологии и терапии, РМАНПО; заведующий отделением клинической фармакологии, ГКБ имени С.С. Юдина.

125993, Москва, ул. Баррикадная, д. 2/1, стр. 1; 115446, Москва, Коломенский проезд, д. 4

Igor N. Sychev - Cand. Sci. (Med.), Associate Professor, Department of Clinical Pharmacology and Therapy, RMACPE; Head of Clinical Pharmacology Department, Yudin CCH.

2/1, Bldg. 1, Barrikadnaya St., Moscow, 125993; 4, Kolomensky Proezd, Moscow, 115446

sychevigor@mail.ruhttps://orcid.org/0000-0003-3278-5941ДенисенкоН. П.DenisenkoN. P.

Денисенко Наталья Павловна - кандидат медицинских наук, заведующая отделом персонализированной медицины.

125284, Москва, Боткинский проезд, д. 7, корп. 2

Natalia P. Denisenko - Cand. Sci. (Med.), Head of Personalized Medicine Department.

7, Bldg. 2, Botkinsky Passages, Moscow, 125284

natalypilipenko3990@gmail.comhttps://orcid.org/0000-0001-9001-1499АбдуллаевШ. П.AbdullaevSh. P.

Абдуллаев Шерзод Пардабоевич - кандидат биологических наук, заведующий отделом молекулярной медицины.

125284, Москва, Боткинский проезд, д. 7, корп. 2

Sherzod P. Abdullaev - Cand. Sci. (Biol.), Head of Molecular Medicine Department.

7, Bldg. 2, Botkinsky Passages, Moscow, 125284

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

Мирзаев Карин Бадавиевич - доктор медицинских наук, проректор по научной работе и инновациям.

125993, Москва, ул. Баррикадная, д. 2/1, стр. 1

Karin B. Mirzaev - Dr. Sci. (Med.), Vice-Rector for Research and Innovations.

2/1, Bldg. 1, Barrikadnaya St., Moscow, 125993

karin05doc@yandex.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.

125993, Москва, ул. Баррикадная, д. 2/1, стр. 1

Dmitry A. Sychev - Dr. Sci. (Med.), Professor, Acad. RAS, Rector, Head of the Department of Clinical Pharmacology and Therapy.

2/1, Bldg. 1, Barrikadnaya St., Moscow, 125993

dmitry.alex.sychev@gmail.comРоссийская медицинская академия непрерывного профессионального образования; Городская клиническая больница имени С.С. ЮдинаРоссияRussian Medical Academy of Continuous Professional Education; Yudin City Clinical Hospital of the Moscow Healthcare DepartmentRussian FederationНаучно-исследовательский центр Российской медицинской академии непрерывного профессионального образованияРоссияResearch Center of the Russian Medical Academy of Continuing Professional EducationRussian FederationРоссийская медицинская академия непрерывного профессионального образованияРоссияRussian Medical Academy of Continuous Professional EducationRussian Federation202322102023016171177Copyright © Федина Л.В., Сычев И.Н., Денисенко Н.П., Абдуллаев Ш.П., Мирзаев К.Б., Сычев Д.А., 20232023Федина Л.В., Сычев И.Н., Денисенко Н.П., Абдуллаев Ш.П., Мирзаев К.Б., Сычев Д.А.Fedina L.V., Sychev I.N., Denisenko N.P., Abdullaev S.P., Mirzaev K.B., Sychev D.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/7814

В течение последних 60 лет антагонисты витамина К (АВК) были основными препаратами, используемыми для длительной пероральной антикоагулянтной терапии. В связи со значительными ограничениями АВК за последнее десятилетие были созданы пероральные антикоагулянты прямого действия (ПОАК). ПОАК имеют предсказуемый фармакокинетический профиль и лишены недостатков, присущих антагонистам витамина К. Апиксабан – пероральный антикоагулянт прямого действия, ингибитор фактора Ха, применяемый для профилактики тромбоэмболических осложнений у пациентов с неклапанной фибрилляцией предсердий (ФП) и тромбозами глубоких вен. Несмотря на использование рекомендованных дозировок, у некоторых пациентов все еще могут наблюдаться кровотечения или отсутствие нужного антикоагулянтного эффекта. С учетом этого крайне важно изучить новые возможности применения прямых оральных антикоагулянтов и спрогнозировать их дозировку при применении в монотерапии или в комбинации с другими препаратами. Кроме того, недавние исследования документально подтвердили индивидуальную вариабельность уровней ПОАК в плазме. Фармакогенетика ПОАК – относительно новая область исследований. Необходимо понять роль фармакогенетики в адаптации антикоагулянтной терапии в соответствии с генетическими особенностями пациента. В этом научном обзоре актуальных данных мы детально описываем особенности фармакокинетики и фармакогенетики апиксабана, а также новые данные, касающиеся клинических характеристик, которые предопределяют необходимую дозировку и риск побочных лекарственных реакций (НЛР). Ведь полученные к настоящему времени результаты фундаментальных и клинических исследований, безусловно, свидетельствуют о неоспоримом влиянии изменений генома на фармакокинетику ПОАК.

For the past 60 years, vitamin K antagonists (VKAs) have been the main drugs used for long-term oral anticoagulant therapy. Because of the significant limitations of AVCs, direct-acting oral anticoagulants (DOAKs) have been developed over the past decade. DOAKs have a predictable pharmacokinetic profile and lack the disadvantages of vitamin K antagonists. Apixaban is an oral direct-acting factor Xa inhibitor used for the prevention of thromboembolic complications in patients with non-valvular atrial fibrillation (AF) and deep vein thrombosis. Despite the use of recommended dosages, some patients may still experience bleeding or lack the desired anticoagulant effect. With this in mind, it is critical to explore new uses for direct oral anticoagulants and to predict their dosage when used in monotherapy or in combination with other drugs. In addition, recent studies have documented individual variability in plasma POAC levels. DOAC pharmacogenetics is a relatively new area of research. There is a need to understand the role of pharmacogenetics in adapting anticoagulant therapy according to a patient’s genetic characteristics. In this scientific review of current data, we detail the pharmacokinetics and pharmacogenetics of apixaban as well as new data concerning the clinical characteristics that predetermine the necessary dosage and risk of adverse drug reactions (ADRs). Indeed, the results obtained to date from basic and clinical studies certainly indicate an undeniable influence of genomic changes on the pharmacokinetics of POACs.

ПОАКфармакогенетикафармакокинетикаперсонализированная медицинафибрилляция предсердийтромбоз глубоких венDOACpharmacogeneticspharmacokineticspersonalized medicineatrial fibrillationdeep vein thrombosisРабота была поддержана грантом РНФ №22-15-00251 «Персонализированное применение прямых оральных антикоагулянтов на основе фармакогеномного подхода»The work was supported by Russian Science Foundation Grant No. 22-15-00251 — Personalized Use of Direct Oral Anticoagulants Based on the Pharmacogenomic ApproachReferencesPalmirotta R. Direct Oral Anticoagulants (DOAC): Are We Ready for a Pharmacogenetic Approach? J Pers Med. 2021;12(1):17. https://doi.org/10.3390/jpm12010017.Palmirotta R. Direct Oral Anticoagulants (DOAC): Are We Ready for a Pharmacogenetic Approach? J Pers Med. 2021;12(1):17. https://doi.org/10.3390/jpm12010017.Duarte JD, Cavallari LH. Pharmacogenetics to Guide Cardiovascular Drug Therapy. Nat Rev Cardiol. 2021;18(9):649–665. https://doi.org/10.1038/s41569-021-00549-w.Duarte JD, Cavallari LH. Pharmacogenetics to Guide Cardiovascular Drug Therapy. Nat Rev Cardiol. 2021;18(9):649–665. https://doi.org/10.1038/s41569-021-00549-w.Ragia G, Manolopoulos VG. Pharmacogenomics of Anticoagulation Therapy: The Last 10 Years. Pharmacogenomics. 2019;20(16):1113–1117. https://doi.org/10.2217/pgs-2019-0149.Ragia G, Manolopoulos VG. Pharmacogenomics of Anticoagulation Therapy: The Last 10 Years. Pharmacogenomics. 2019;20(16):1113–1117. https://doi.org/10.2217/pgs-2019-0149.Camm AJ, Fox KAA, Virdone S, Bassand JP, Fitzmaurice DA, Berchuck SI et al; GARFIELD-AF investigators. Comparative Effectiveness of Oral Anticoagulants in Everyday Practice. Heart. 2021;107(12):962–970. https://doi.org/10.1136/heartjnl-2020-318420.Camm AJ, Fox KAA, Virdone S, Bassand JP, Fitzmaurice DA, Berchuck SI et al; GARFIELD-AF investigators. Comparative Effectiveness of Oral Anticoagulants in Everyday Practice. Heart. 2021;107(12):962–970. https://doi.org/10.1136/heartjnl-2020-318420.Shnayder NA, Petrova MM, Shesternya PA, Savinova AV, Bochanova EN, Zimnitskaya OV et al. Using Pharmacogenetics of Direct Oral Anticoagulants to Predict Changes in Their Pharmacokinetics and the Risk of Adverse Drug Reactions. Biomedicines 2021;9(5):451. https://doi.org/10.3390/biomedicines9050451.Shnayder NA, Petrova MM, Shesternya PA, Savinova AV, Bochanova EN, Zimnitskaya OV et al. Using Pharmacogenetics of Direct Oral Anticoagulants to Predict Changes in Their Pharmacokinetics and the Risk of Adverse Drug Reactions. Biomedicines 2021;9(5):451. https://doi.org/10.3390/biomedicines9050451.Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361(12):1139–1151. https://doi.org/10.1056/NEJMoa0905561.Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361(12):1139–1151. https://doi.org/10.1056/NEJMoa0905561.Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 2011;365(10):883–891. https://doi.org/10.1056/NEJMoa1009638.Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 2011;365(10):883–891. https://doi.org/10.1056/NEJMoa1009638.Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M et al.; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–992. https://doi.org/10.1056/NEJMoa1107039.Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M et al.; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–992. https://doi.org/10.1056/NEJMoa1107039.van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124(12):1968–1975. https://doi.org/10.1182/blood-2014-04-571232.van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124(12):1968–1975. https://doi.org/10.1182/blood-2014-04-571232.Geller AI, Shehab N, Lovegrove MC, Rose KO, Weidle NJ, Goring SK, Budnitz DS. Emergency Visits for Oral Anticoagulant Bleeding. J Gen Intern Med. 2020;35(1):371–373. https://doi.org/10.1007/s11606-019-05391-y.Geller AI, Shehab N, Lovegrove MC, Rose KO, Weidle NJ, Goring SK, Budnitz DS. Emergency Visits for Oral Anticoagulant Bleeding. J Gen Intern Med. 2020;35(1):371–373. https://doi.org/10.1007/s11606-019-05391-y.Shehab N, Lovegrove MC, Geller AI, Rose KO, Weidle NJ, Budnitz DS. US Emergency Department Visits for Outpatient Adverse Drug Events, 2013–2014. JAMA. 2016;316(20):2115–2125. https://doi.org/10.1001/jama.2016.16201.Shehab N, Lovegrove MC, Geller AI, Rose KO, Weidle NJ, Budnitz DS. US Emergency Department Visits for Outpatient Adverse Drug Events, 2013–2014. JAMA. 2016;316(20):2115–2125. https://doi.org/10.1001/jama.2016.16201.Скрипка АИ, Когай ВВ, Листратов АИ, Соколова АА, Напалков ДА, Фомин ВВ. Персонализированный подход к назначению прямых оральных антикоагулянтов: от теории к практике. Терапевтический архив. 2019;91(7):111–120. https://doi.org/10.26442/00403660.2019.07.000045.Skripka AI, Kogay VV, Listratov AI, Sokolova AA, Napalkov DA, Fomin VV. Personalized approach for direct oral anticoagulant prescription: from theory to practice. Terapevticheskii Arkhiv. 2019;91(7):111–120. (In Russ.) https://doi.org/10.26442/00403660.2019.07.000045.Luettgen JM, Knabb RM, He K, Pinto DJ, Rendina AR. Apixaban inhibition of factor Xa: Microscopic rate constants and inhibition mechanism in purified protein systems and in human plasma. J Enzyme Inhib Med Chem. 2011;26(4):514–526. https://doi.org/10.3109/14756366.2010.535793.Luettgen JM, Knabb RM, He K, Pinto DJ, Rendina AR. Apixaban inhibition of factor Xa: Microscopic rate constants and inhibition mechanism in purified protein systems and in human plasma. J Enzyme Inhib Med Chem. 2011;26(4):514–526. https://doi.org/10.3109/14756366.2010.535793.Jiang X, Crain EJ, Luettgen JM, Schumacher WA, Wong PC. Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xa activity in vitro. Thromb Haemost. 2009;101(4):780–782. Available at: https://pubmed.ncbi.nlm.nih.gov/19350128.Jiang X, Crain EJ, Luettgen JM, Schumacher WA, Wong PC. Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xa activity in vitro. Thromb Haemost. 2009;101(4):780–782. Available at: https://pubmed.ncbi.nlm.nih.gov/19350128.Wong PC, Pinto DJ, Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis. 2011;31(4):478–492. https://doi.org/10.1007/s11239-011-0551-3.Wong PC, Pinto DJ, Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis. 2011;31(4):478–492. https://doi.org/10.1007/s11239-011-0551-3.Raghavan N, Frost CE, Yu Z, He K, Zhang H, Humphreys WG et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37(1):74–81. https://doi.org/10.1124/dmd.108.023143.Raghavan N, Frost CE, Yu Z, He K, Zhang H, Humphreys WG et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37(1):74–81. https://doi.org/10.1124/dmd.108.023143.Wang L, Raghavan N, He K, Luettgen JM, Humphreys WG, Knabb RM et al. Sulfation of o-demethyl apixaban: enzyme identification and species comparison. Drug Metab Dispos. 2009;37(4):802–808. https://doi.org/10.1124/dmd.108.025593.Wang L, Raghavan N, He K, Luettgen JM, Humphreys WG, Knabb RM et al. Sulfation of o-demethyl apixaban: enzyme identification and species comparison. Drug Metab Dispos. 2009;37(4):802–808. https://doi.org/10.1124/dmd.108.025593.Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review. Clin Pharmacokinet. 2019;58(10):1265–1279. https://doi.org/10.1007/s40262-019-00775-z.Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review. Clin Pharmacokinet. 2019;58(10):1265–1279. https://doi.org/10.1007/s40262-019-00775-z.Shehab N, Lovegrove MC, Geller AI, Rose KO, Weidle NJ, Budnitz DS. US Emergency Department Visits for Outpatient Adverse Drug Events, 2013–2014. JAMA. 2016;316(20):2115–2125. https://doi.org/10.1001/jama.2016.16201.Shehab N, Lovegrove MC, Geller AI, Rose KO, Weidle NJ, Budnitz DS. US Emergency Department Visits for Outpatient Adverse Drug Events, 2013–2014. JAMA. 2016;316(20):2115–2125. https://doi.org/10.1001/jama.2016.16201.Baglin TP, Cousins D, Keeling DM, Perry DJ, Watson HG. Safety indicators for inpatient and outpatient oral anticoagulant care: [corrected] Recommendations from the British Committee for Standards in Haematology and National Patient Safety Agency. Br J Haematol. 2007;136(1):26–29. https://doi.org/10.1111/j.1365-2141.2006.06379.x.Baglin TP, Cousins D, Keeling DM, Perry DJ, Watson HG. Safety indicators for inpatient and outpatient oral anticoagulant care: [corrected] Recommendations from the British Committee for Standards in Haematology and National Patient Safety Agency. Br J Haematol. 2007;136(1):26–29. https://doi.org/10.1111/j.1365-2141.2006.06379.x.Lip GYH, Banerjee A, Boriani G, Chiang CE, Fargo R, Freedman B et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest. 2018;154(5):1121–1201. https://doi.org/10.1016/j.chest.2018.07.040.Lip GYH, Banerjee A, Boriani G, Chiang CE, Fargo R, Freedman B et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest. 2018;154(5):1121–1201. https://doi.org/10.1016/j.chest.2018.07.040.Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL et al.; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–2104. https://doi.org/10.1056/NEJMoa1310907.Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL et al.; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–2104. https://doi.org/10.1056/NEJMoa1310907.Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med. 2013;368(14):1272–1274. https://doi:10.1056/NEJMp1302834.Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med. 2013;368(14):1272–1274. https://doi:10.1056/NEJMp1302834.Overvad TF, Larsen TB, Albertsen IE, Rasmussen LH, Lip GY. Balancing bleeding and thrombotic risk with new oral anticoagulants in patients with atrial fibrillation. Expert Rev Cardiovasc Ther. 2013;11(12):1619–1629. https://doi.org/10.1586/14779072.2013.839214.Overvad TF, Larsen TB, Albertsen IE, Rasmussen LH, Lip GY. Balancing bleeding and thrombotic risk with new oral anticoagulants in patients with atrial fibrillation. Expert Rev Cardiovasc Ther. 2013;11(12):1619–1629. https://doi.org/10.1586/14779072.2013.839214.Padrini R. Clinical Pharmacokinetics and Pharmacodynamics of Direct Oral Anticoagulants in Patients with Renal Failure. Eur J Drug Metab Pharmacokinet. 2019;44(1):1–12. https://doi.org/10.1007/s13318-018-0501-y.Padrini R. Clinical Pharmacokinetics and Pharmacodynamics of Direct Oral Anticoagulants in Patients with Renal Failure. Eur J Drug Metab Pharmacokinet. 2019;44(1):1–12. https://doi.org/10.1007/s13318-018-0501-y.Cohen D. Concerns over data in key dabigatran trial. BMJ. 2014;349:g4747. https://doi.org/10.1136/bmj.g4747.Cohen D. Concerns over data in key dabigatran trial. BMJ. 2014;349:g4747. https://doi.org/10.1136/bmj.g4747.Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S et al.; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806–817.https://doi.org/10.1056/NEJMoa1007432.Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S et al.; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806–817.https://doi.org/10.1056/NEJMoa1007432.Sebaaly J, Kelley D. Direct Oral Anticoagulants in Obesity: An Updated Literature Review. Ann Pharmacother. 2020;54(11):1144–1158. https://doi.org/10.1177/1060028020923584.Sebaaly J, Kelley D. Direct Oral Anticoagulants in Obesity: An Updated Literature Review. Ann Pharmacother. 2020;54(11):1144–1158. https://doi.org/10.1177/1060028020923584.Chang M, Yu Z, Shenker A, Wang J, Pursley J, Byon W et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol. 2016;56(5):637–645. https://doi.org/10.1002/jcph.633.Chang M, Yu Z, Shenker A, Wang J, Pursley J, Byon W et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol. 2016;56(5):637–645. https://doi.org/10.1002/jcph.633.Сычев ИН, Федина ЛВ, Габриелян ДА, Растворова ТД, Стригункова ЕВ, Мирзаев КБ, Сычев ДА. Антикоагулянтная терапия прямыми пероральными антикоагулянтами в условиях полипрагмазии: курс на безопасность. Медицинский совет. 2022;(17):52–64. https://doi.org/10.21518/2079-701X-2022-16-17-52-64.Sychev IN, Fedina LV, Gabrielyan DA, Rastvorova TD, Strigunkova EV, Mirzayev KB, Sychev DA. Anticoagulant therapy with direct oral anticoagulants in the context of polypragmasy: a course to safety. Meditsinskiy Sovet. 2022;(17):52–64. (In Russ.) https://doi.org/10.21518/2079-701X-2022-16-17-52-64.Ašić A, Marjanović D, Mirat J, Primorac D. Pharmacogenetics of Novel Oral Anticoagulants: A Review of Identified Gene Variants & Future Perspectives. Per Med. 2018;15(3):209–221. https://doi.org/10.2217/pme-2017-0092.Ašić A, Marjanović D, Mirat J, Primorac D. Pharmacogenetics of Novel Oral Anticoagulants: A Review of Identified Gene Variants & Future Perspectives. Per Med. 2018;15(3):209–221. https://doi.org/10.2217/pme-2017-0092.Vakkalagadda B, Frost C, Byon W, Boyd RA, Wang J, Zhang D et al. Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa. Am J Cardiovasc Drugs. 2016;16(2):119–127. https://doi.org/:10.1007/ s40256-015-0157-9.Vakkalagadda B, Frost C, Byon W, Boyd RA, Wang J, Zhang D et al. Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa. Am J Cardiovasc Drugs. 2016;16(2):119–127. https://doi.org/:10.1007/ s40256-015-0157-9.Frost CE, Byon W, Song Y, Wang J, Schuster AE, Boyd RA et al. Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Br J Clin Pharmacol. 2015;79(5):838–846. https://doi.org/:10.1111/bcp.12541.Frost CE, Byon W, Song Y, Wang J, Schuster AE, Boyd RA et al. Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Br J Clin Pharmacol. 2015;79(5):838–846. https://doi.org/:10.1111/bcp.12541.Mikus G, Foerster KI, Schaumaeker M, Lehmann ML, Burhenne J, Haefeli WE. Application of a microdosed cocktail of 3 oral factor Xa inhibitors to study drug-drug interactions with different perpetrator drugs. Br J Clin Pharmacol. 2020;86(8):1632–1641. https://doi.org/10.1111/bcp.14277.Mikus G, Foerster KI, Schaumaeker M, Lehmann ML, Burhenne J, Haefeli WE. Application of a microdosed cocktail of 3 oral factor Xa inhibitors to study drug-drug interactions with different perpetrator drugs. Br J Clin Pharmacol. 2020;86(8):1632–1641. https://doi.org/10.1111/bcp.14277.Sodhi JK, Liu S, Benet LZ. Intestinal Efflux Transporters P-gp and BCRP Are Not Clinically Relevant in Apixaban Disposition. Pharm Res. 2020;37(10):208. https://doi.org/10.1007/s11095-020-02927-4.Sodhi JK, Liu S, Benet LZ. Intestinal Efflux Transporters P-gp and BCRP Are Not Clinically Relevant in Apixaban Disposition. Pharm Res. 2020;37(10):208. https://doi.org/10.1007/s11095-020-02927-4.Mar PL, Gopinathannair R, Gengler BE, Chung MK, Perez A, Dukes J et al.; from the American Heart Association Electrocardiography & Arrhythmias Committee of the Council of Clinical Cardiology. Drug Interactions Affecting Oral Anticoagulant Use. Circ Arrhythm Electrophysiol. 2022;15(6):e007956. https://doi.org/10.1161/CIRCEP.121.007956.Mar PL, Gopinathannair R, Gengler BE, Chung MK, Perez A, Dukes J et al.; from the American Heart Association Electrocardiography & Arrhythmias Committee of the Council of Clinical Cardiology. Drug Interactions Affecting Oral Anticoagulant Use. Circ Arrhythm Electrophysiol. 2022;15(6):e007956. https://doi.org/10.1161/CIRCEP.121.007956.Hill K, Sucha E, Rhodes E, Carrier M, Garg AX, Harel Z et al. Risk of Hospitalization With Hemorrhage Among Older Adults Taking Clarithromycin vs Azithromycin and Direct Oral Anticoagulants. JAMA Intern Med. 2020;180(8):1052–1060. https://doi.org/10.1001/jamainternmed.2020.1835.Hill K, Sucha E, Rhodes E, Carrier M, Garg AX, Harel Z et al. Risk of Hospitalization With Hemorrhage Among Older Adults Taking Clarithromycin vs Azithromycin and Direct Oral Anticoagulants. JAMA Intern Med. 2020;180(8):1052–1060. https://doi.org/10.1001/jamainternmed.2020.1835.Washam JB, Hohnloser SH, Lopes RD, Wojdyla DM, Vinereanu D, Alexander JH et al.; ARISTOTLE Committees and Investigators. Interacting medication use and the treatment effects of apixaban versus warfarin: results from the ARISTOTLE Trial. J Thromb Thrombolysis. 2019;47(3):345–352. https://doi.org/10.1007/s11239-019-01823-y.Washam JB, Hohnloser SH, Lopes RD, Wojdyla DM, Vinereanu D, Alexander JH et al.; ARISTOTLE Committees and Investigators. Interacting medication use and the treatment effects of apixaban versus warfarin: results from the ARISTOTLE Trial. J Thromb Thrombolysis. 2019;47(3):345–352. https://doi.org/10.1007/s11239-019-01823-y.Сычев ИН, Федина ЛВ, Осипов АС, Темирбулатов ИИ, Татарой ОЮ, Созаева ЖА и др. Влияние полиморфизмов генов CYP3A4*22 (rs35599367) C > T, CYP3A5*3 (rs776746) A > G, ABCB1 (rs4148738) C > T и ABCB1 (rs1045642) C > T на антикоагулянтное действие апиксабана: результаты пилотного исследования. Медицинский совет. 2021;(4):41–46. https://doi.org/10.21518/2079-701X-2021-4-41-46.Sychev IN, Fedina LV, Osipov AS, Temirbulatov II, Tataroy OYu, Sozaeva ZA et al. Effect of polymorphisms in CYP3A4*22 (rs35599367) C > T, CYP3A5*3 (rs776746) A > G, ABCB1 (rs4148738) C > T and ABCB1 (rs1045642) C > T genes on apixaban anticoagulation: pilot study results. Meditsinskiy Sovet. 2021;(4):41–46. (In Russ.) https://doi.org/10.21518/2079-701X-2021-4-41-46.Ueshima S, Hira D, Fujii R, Kimura Y, Tomitsuka C, Yamane T et al. Impact of ABCB1, ABCG2, and CYP3A5 polymorphisms on plasma trough concentrations of apixaban in Japanese patients with atrial fibrillation. Pharmacogenet Genomics. 2017;27(9):329–336. https://doi.org/10.1097/FPC.0000000000000294.Ueshima S, Hira D, Fujii R, Kimura Y, Tomitsuka C, Yamane T et al. Impact of ABCB1, ABCG2, and CYP3A5 polymorphisms on plasma trough concentrations of apixaban in Japanese patients with atrial fibrillation. Pharmacogenet Genomics. 2017;27(9):329–336. https://doi.org/10.1097/FPC.0000000000000294.Attelind S, Hallberg P, Wadelius M, Hamberg AK, Siegbahn A, Granger CB et al. Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events. Front Genet. 2022;13:982955. https://doi.org/10.3389/fgene.2022.982955.Attelind S, Hallberg P, Wadelius M, Hamberg AK, Siegbahn A, Granger CB et al. Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events. Front Genet. 2022;13:982955. https://doi.org/10.3389/fgene.2022.982955.Савинова АВ, Петрова ММ, Шнайдер НА, Бочанова ЕН, Насырова РФ. Фармакокинетика и фармакогенетика апиксабана. Рациональная фармакотерапия в кардиологии. 2020;16(5):852–860. https://doi.org/10.20996/1819-6446-2020-10-17.Savinova AV, Petrova MM, Shnayder NA, Bochanova EN, Nasyrova RF. Pharmacokinetics and Pharmacogenetics of Apixaban. Rational Pharmacotherapy in Cardiology. 2020;16(5):852–860. (In Russ.) https://doi.org/10.20996/1819-6446-2020-10-17.Kang RH, Jung SM, Kim KA, Lee DK, Cho HK, Jung BJ et al. Effects of CYP2D6 and CYP3A5 genotypes on the plasma concentrations of risperidone and 9-hydroxyrisperidone in Korean schizophrenic patients. J Clin Psychopharmacol. 2009;29(3):272–277. https://doi.org/10.1097/JCP.0b013e3181a289e0.Kang RH, Jung SM, Kim KA, Lee DK, Cho HK, Jung BJ et al. Effects of CYP2D6 and CYP3A5 genotypes on the plasma concentrations of risperidone and 9-hydroxyrisperidone in Korean schizophrenic patients. J Clin Psychopharmacol. 2009;29(3):272–277. https://doi.org/10.1097/JCP.0b013e3181a289e0.Kryukov AV, Sychev DA, Andreev DA, Ryzhikova KA, Grishina EA, Ryabova AV et al. Influence of ABCB1 and CYP3A5 gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke. Pharmgenomics Pers Med. 2018;11:43–49. https://doi.org/10.2147/PGPM.S157111.Kryukov AV, Sychev DA, Andreev DA, Ryzhikova KA, Grishina EA, Ryabova AV et al. Influence of ABCB1 and CYP3A5 gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke. Pharmgenomics Pers Med. 2018;11:43–49. https://doi.org/10.2147/PGPM.S157111.Dimatteo C, D’Andrea G, Vecchione G, Paoletti O, Tiscia GL, Santacroce R et al. ABCB1 SNP rs4148738 modulation of apixaban interindividual variability. Thromb Res. 2016;145:24–26. https://doi.org/10.1016/j.thromres.2016.07.005.Dimatteo C, D’Andrea G, Vecchione G, Paoletti O, Tiscia GL, Santacroce R et al. ABCB1 SNP rs4148738 modulation of apixaban interindividual variability. Thromb Res. 2016;145:24–26. https://doi.org/10.1016/j.thromres.2016.07.005.Lähteenmäki J, Vuorinen AL, Pajula J, Harno K, Lehto M, Niemi M, van Gils M. Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users. Clin Pharmacol Ther. 2021;110(3):768–776. https://doi.org/10.1002/cpt.2316.Lähteenmäki J, Vuorinen AL, Pajula J, Harno K, Lehto M, Niemi M, van Gils M. Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users. Clin Pharmacol Ther. 2021;110(3):768–776. https://doi.org/10.1002/cpt.2316.Shnayder NA, Petrova MM, Shesternya PA, Savinova AV, Bochanova EN, Zimnitskaya OV et al. Using Pharmacogenetics of Direct Oral Anticoagulants to Predict Changes in Their Pharmacokinetics and the Risk of Adverse Drug Reactions. Biomedicines. 2021;9(5):451. https://doi.org/10.3390/biomedicines9050451.Shnayder NA, Petrova MM, Shesternya PA, Savinova AV, Bochanova EN, Zimnitskaya OV et al. Using Pharmacogenetics of Direct Oral Anticoagulants to Predict Changes in Their Pharmacokinetics and the Risk of Adverse Drug Reactions. Biomedicines. 2021;9(5):451. https://doi.org/10.3390/biomedicines9050451.

The authors declare that there are no conflicts of interest present.