{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:08:57Z","timestamp":1788952137140,"version":"build-2803163510"},"reference-count":58,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"crossref","award":["075-15-2025-463"],"award-info":[{"award-number":["075-15-2025-463"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["25-25-00148"],"award-info":[{"award-number":["25-25-00148"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Direct oral anticoagulants (DOACs) have transformed the prevention of thromboembolic events, but their efficacy and safety remain highly variable across individuals. DD217, a novel oral direct factor Xa inhibitor, has demonstrated potent anticoagulant activity in preclinical and clinical studies. No pharmacogenetic data are currently available for this compound. Based on in silico predictions of metabolic pathways and transporter involvement, and evidence from other DOACs, we hypothesized that variants in CYP2C and P-glycoprotein genes may contribute to variability in pharmacokinetics (PK) and clinical outcomes. Methods: Fifty-two patients undergoing total knee arthroplasty were enrolled, of whom 34 received the investigational drug (40 mg\/day, n = 16; 60 mg\/day, n = 18). DNA was extracted from peripheral blood cells, and genotyping of CYP2C9, CYP2C19, CYP2C8, CYP3A4, CYP3A5, and ABCB1 was performed by real-time PCR. Pharmacokinetics (PK) parameters (Tmax, AUClast, Cmax) were assessed. In silico docking and pathway modeling predicted CYP2C and P-glycoprotein (ABCB1) involvement in drug disposition. Associations of genetic variants with PK parameters and adverse events (thrombosis, bleeding) were analyzed. Results: Carriers of reduced-function CYP2C9 alleles (intermediate [IM] or poor metabolizers [PM]) in the 60 mg group had a significantly shorter Tmax compared with normal metabolizers (p = 0.005227), with trends toward higher AUClast (p = 0.06926) and Cmax (p = 0.1259). No significant associations were observed for CYP2C19, CYP3A4\/5, or CYP2C8. In contrast, ABCB1 polymorphisms were associated with systemic exposure: carriers of the C allele at rs1045642 had higher AUClast and Cmax compared to TT (wild-type) homozygotes, while rs2032582 T allele carriers showed lower exposure (p &lt; 0.05). At the haplotype level, the C\u2013G\u2013C\u2013T combination of ABCB1 was more frequent in patients with thrombotic events at the 40 mg dose (p = 0.038). Overall, 5 thrombosis events and 1 bleedings were recorded on DD217, with no consistent associations to single SNPs. Conclusions: This first pharmacogenetic evaluation of DD217 shows that CYP2C9 variants are associated with differences in early-phase pharmacokinetics (Tmax), while ABCB1 polymorphisms appear to modulate systemic exposure (AUClast, Cmax) and may influence thrombotic risk. These observations are consistent with in silico predictions of metabolic and transporter pathways. Despite limitations in sample size and event frequency, the study highlights the feasibility and importance of early pharmacogenetic evaluation during the drug development cycle of novel DOACs.<\/jats:p>","DOI":"10.3390\/ph18111617","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T11:47:19Z","timestamp":1761652039000},"page":"1617","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["An Investigational Study on the Role of ADME Agents\u2019 Genetic Variation on DD217 Pharmacokinetics and Safety Profile"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4496-3680","authenticated-orcid":false,"given":"Dmitry A.","family":"Sychev","sequence":"first","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Abrikosovsky Lane, 2, 119991 Moscow, Russia"},{"name":"Federal State Budgetary Educational Institution of Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d of the Ministry of Healthcare of the Russian Federation, Barrikadnaya Str. 2\/1, Bld. 1, 125993 Moscow, 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, Abrikosovsky Lane, 2, 119991 Moscow, Russia"},{"name":"Federal State Budgetary Educational Institution of Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d of the Ministry of Healthcare of the Russian Federation, Barrikadnaya Str. 2\/1, Bld. 1, 125993 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8916-9675","authenticated-orcid":false,"given":"Anastasia V.","family":"Rudik","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Chemistry, Bldg. 8, 10, Pogodinskaya Str., 119121 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2431-3429","authenticated-orcid":false,"given":"Alexander V.","family":"Dmitriev","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Chemistry, Bldg. 8, 10, Pogodinskaya Str., 119121 Moscow, 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, Abrikosovsky Lane, 2, 119991 Moscow, Russia"},{"name":"Federal State Budgetary Educational Institution of Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d of the Ministry of Healthcare of the Russian Federation, Barrikadnaya Str. 2\/1, Bld. 1, 125993 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3278-5941","authenticated-orcid":false,"given":"Natalia P.","family":"Denisenko","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Abrikosovsky Lane, 2, 119991 Moscow, Russia"},{"name":"Federal State Budgetary Educational Institution of Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d of the Ministry of Healthcare of the Russian Federation, Barrikadnaya Str. 2\/1, Bld. 1, 125993 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis S.","family":"Makarov","sequence":"additional","affiliation":[{"name":"Avexima Diol LLC, 690922 Vladivostok, 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, Abrikosovsky Lane, 2, 119991 Moscow, Russia"},{"name":"Federal State Budgetary Educational Institution of Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d of the Ministry of Healthcare of the Russian Federation, Barrikadnaya Str. 2\/1, Bld. 1, 125993 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/nrcardio.2015.83","article-title":"Epidemiology of venous thromboembolism","volume":"12","author":"Heit","year":"2015","journal-title":"Nat. Rev. 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