{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:04:19Z","timestamp":1789535059651,"version":"build-2803163510"},"reference-count":16,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Pers. Med.","JPM"],"abstract":"<jats:p>Background: The administration of direct oral anticoagulants to older adults requires careful risk stratification against a backdrop of polypharmacy and age-related renal function decline. The role of single nucleotide polymorphisms in cytochrome P450 genes and efflux transporters in this context remains a clinically understudied issue. This study aimed to investigate the association of ABCB1, CYP3A4, and CYP3A5 allelic variants with the safety of rivaroxaban therapy in geriatric patients with non-valvular atrial fibrillation (AF). Materials and Methods: This prospective cohort study consecutively enrolled 94 patients (mean age 83.2 \u00b1 9.2 years). Rivaroxaban trough plasma concentrations (Cmin,ss ) were quantified using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS\/MS) assay. Real-time polymerase chain reaction was utilized for the molecular genetic profiling of the ABCB1 (rs1045642, rs2032582), CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746) loci. Comorbidity severity and the spectrum of drug\u2013drug interactions were evaluated as additional predictors. Results: Clinically relevant hemorrhagic complications were documented in 36.2% (n = 34) of the monitored patients. A significant association was established between the homozygous CC genotype at the ABCB1 rs1045642 locus and increased bleeding propensity (odds ratio [OR] 2.42; 95% CI: 1.02\u20135.74; p = 0.042), whereas the alternative TT variant was associated with a pronounced protective effect. No statistically significant correlations were identified for biotransformation isoenzyme markers (CYP3A4*22, CYP3A5*3). Anticoagulant metrics were comparably distributed across groups and showed no dependence on genetic status. The leading non-genetic factors associated with hemorrhage were advanced age (p &lt; 0.0001), progressive glomerular filtration rate decline (CKD stages 3b\u20134; p = 0.0009), and pharmacokinetic\/pharmacodynamic interference from the co-administration of amiodarone (OR 3.61), non-steroidal anti-inflammatory drugs, and antiplatelet agents. The validated HAS-BLED score demonstrated no predictive power within the comorbid conditions of this cohort (p = 0.052). Conclusions: The ABCB1 rs1045642 (C3435T) polymorphism is associated with the occurrence of hemorrhagic events. Implementing pharmacogenetic testing of the P-glycoprotein transporter combined with a rigorous audit of renal excretory function and concomitant therapy management may optimize the safety profile of rivaroxaban in geriatric practice. These findings warrant confirmation in a larger cohort.<\/jats:p>","DOI":"10.3390\/jpm16090470","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:09:51Z","timestamp":1789387791000},"page":"470","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of Cytochrome P450 and P-glycoprotein Gene Polymorphisms on the Risk of Hemorrhagic Complications in Older Patients with Non-Valvular Atrial Fibrillation Treated with Rivaroxaban"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0227-2651","authenticated-orcid":false,"given":"Ivan V.","family":"Sychev","sequence":"first","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey P.","family":"Kondrakhin","sequence":"additional","affiliation":[{"name":"Moscow Healthcare Department, War Veterans Hospital No. 2, Moscow 109472, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9001-1499","authenticated-orcid":false,"given":"Sherzod P.","family":"Abdullaev","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Moscow 119991, Russia"},{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8555-5969","authenticated-orcid":false,"given":"Pavel O.","family":"Bochkov","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2744-2752","authenticated-orcid":false,"given":"Svetlana N.","family":"Tuchkova","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Moscow 119991, Russia"},{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyubov V.","family":"Selivanova","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5516-7367","authenticated-orcid":false,"given":"Denis S.","family":"Fedorinov","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Moscow 119991, Russia"},{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"},{"name":"Moscow Multidisciplinary Clinical Center \u201cKommunarka\u201d, Moscow 108814, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga A.","family":"Milovanova","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin B.","family":"Mirzaev","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Moscow 119991, Russia"},{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4496-3680","authenticated-orcid":false,"given":"Dmitry A.","family":"Sychev","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Moscow 119991, Russia"},{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1093\/eurheartj\/ehae176","article-title":"2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS)","volume":"45","author":"Rienstra","year":"2024","journal-title":"Eur. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.jacc.2023.08.017","article-title":"2023 ACC\/AHA\/ACCP\/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"83","author":"Joglar","year":"2024","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.jacc.2010.09.024","article-title":"Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: The HAS-BLED (Hypertension, Abnormal Renal\/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs\/Alcohol Concomitantly) score","volume":"57","author":"Lip","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Hwang, H.J., Sohn, I.S., Jin, E.S., and Bae, Y.J. (2023). Adherence and clinical outcomes for twice-daily versus once-daily dosing of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: Is dosing frequency important?. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0283478"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40262-013-0100-7","article-title":"Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban","volume":"53","author":"Mueck","year":"2014","journal-title":"Clin. Pharmacokinet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"470","DOI":"10.20996\/1819-6446-2023-2970","article-title":"Pharmacogenetics and pharmacokinetics of rivaroxaban in patients with atrial fibrillation and chronic kidney disease","volume":"19","author":"Shatalova","year":"2023","journal-title":"Ration. Pharmacother. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s40292-022-00536-3","article-title":"The Influence of ABCB1 (rs1045642 and rs4148738) Gene Polymorphisms on Rivaroxaban Pharmacokinetics in Patients Aged 80 Years and Older with Nonvalvular Atrial Fibrillation","volume":"29","author":"Sychev","year":"2022","journal-title":"High Blood Press. Cardiovasc. Prev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1097\/FPC.0000000000000483","article-title":"Influence of ABCB1, CYP3A5 and CYP3A4 gene polymorphisms on prothrombin time and the residual equilibrium concentration of rivaroxaban in patients with non-valvular atrial fibrillation in real clinical practice","volume":"32","author":"Sychev","year":"2022","journal-title":"Pharmacogenet. Genom."},{"key":"ref_9","first-page":"51","article-title":"Features of drug-drug interactions between rivaroxaban and calcium channel blockers depending on the ABCB1 (rs1045642 and rs4148738) genotype in patients 80 years of age and older with non-valvular atrial fibrillation","volume":"8","author":"Sychev","year":"2023","journal-title":"Acta Biomed. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1056\/NEJMoa1009638","article-title":"Rivaroxaban versus warfarin in nonvalvular atrial fibrillation","volume":"365","author":"Patel","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_11","unstructured":"(2005). Good Clinical Practice (Standard No. GOST R 52379-2005)."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Deng, K., Cheng, J., Rao, S., Xu, H., Li, L., and Gao, Y. (2020). Efficacy and Safety of Direct Oral Anticoagulants in Elderly Patients With Atrial Fibrillation: A Network Meta-Analysis. Front. Med., 7.","DOI":"10.3389\/fmed.2020.00107"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wang, F., Li, Z., Huang, Y., Liu, Q., Zhao, L., Wang, H., Gao, H., Chen, M., Lin, Y., and Li, X. (2025). Effect of ABCB1 SNP polymorphisms on the plasma concentrations and clinical outcomes of rivaroxaban in Chinese NVAF patients: A population pharmacokinetic-based study. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1574949"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/j.1365-2125.2012.04181.x","article-title":"Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes","volume":"74","author":"Xu","year":"2012","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1097\/FPC.0000000000000402","article-title":"Cis-acting regulatory elements regulating CYP3A4 transcription in human liver","volume":"30","author":"Collins","year":"2020","journal-title":"Pharmacogenet. Genom."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1001\/jama.2017.13883","article-title":"Association Between Use of Non-Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding in Nonvalvular Atrial Fibrillation","volume":"318","author":"Chang","year":"2017","journal-title":"JAMA"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/16\/9\/470\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T04:30:51Z","timestamp":1789533051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/16\/9\/470"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":16,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["jpm16090470"],"URL":"https:\/\/doi.org\/10.3390\/jpm16090470","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,14]]}}}