{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T23:33:19Z","timestamp":1788305599292,"version":"build-2803163510"},"reference-count":19,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T00:00:00Z","timestamp":1648080000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004326","name":"Bayer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004326","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>To evaluate BAY 2433334, an oral activated factor XI (FXIa) inhibitor, in volunteers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Phase 1 study of healthy men at a German centre. Part A: randomized, single\u2010blind, multiple dose\u2010escalation study of BAY 2433334 (25\/50\/100\u2009mg once daily [OD])\n                      <jats:italic>vs<\/jats:italic>\n                      . placebo. Part B: similar design to Part A; evaluated BAY 2433334 25\u2009mg twice daily. Part C: nonrandomized, open\u2010label study; evaluated potential interactions between BAY 2433334 (25\/75\u2009mg OD) and midazolam (7.5\u00a0mg), a CYP3A4 index substrate. Primary variables: treatment\u2010emergent adverse events (TEAEs; Parts A and B); area under the plasma concentration\u2013time curve (AUC) and maximum plasma concentration of midazolam and \u03b1\u2010hydroxymidazolam (Part C). Study period: 18\u2009days plus follow\u2010up visit.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Parts A and B: 36 participants randomized to BAY 2433334; 12 to placebo. Part C: 48 participants assigned to BAY 2433334 plus midazolam. BAY 2433334 was well tolerated in all study parts. AUC and maximum plasma concentration of BAY 2433334 in plasma appeared dose proportional over 25\u2013100\u2009mg OD, with low\u2010to\u2010moderate variability in pharmacokinetic parameters. Multiple dosing caused minor\u2010to\u2010moderate accumulation and a mean terminal half\u2010life (15.8\u201317.8\u00a0h) supporting once\u2010daily dosing. Dose\u2010dependent FXIa activity inhibition and activated partial thromboplastin time prolongation were observed. BAY 2433334 appeared to have a minor effect on AUC for midazolam (ratio [90% confidence interval]: 1.1736 [1.0963\u20131.2564]) and \u03b1\u2010hydroxymidazolam (0.9864 [0.9169\u20131.0612]) only for BAY 2433334 75\u2009mg OD on day 10.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Multiple dosing of BAY 2433334 in healthy volunteers was well tolerated, with a predictable pharmacokinetic\/pharmacodynamic profile and no clinically relevant CYP3A4 induction or inhibition.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bcp.15230","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T02:16:50Z","timestamp":1641867410000},"page":"3447-3462","source":"Crossref","is-referenced-by-count":65,"title":["Pharmacokinetics, pharmacodynamics and safety of BAY 2433334, a novel activated factor XI inhibitor, in healthy volunteers: A randomized phase 1 multiple\u2010dose study"],"prefix":"10.1111","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8450-473X","authenticated-orcid":false,"given":"Dagmar","family":"Kubitza","sequence":"first","affiliation":[{"name":"Bayer AG  Wuppertal Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Heckmann","sequence":"additional","affiliation":[{"name":"Bayer AG  Wuppertal Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Distler","sequence":"additional","affiliation":[{"name":"ClinStat GmbH  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemone","family":"Koechel","sequence":"additional","affiliation":[{"name":"CRS Clinical Research Services Wuppertal GmbH  Wuppertal Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Schwers","sequence":"additional","affiliation":[{"name":"Bayer AG  Wuppertal Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Kanefendt","sequence":"additional","affiliation":[{"name":"Bayer AG  Wuppertal Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,24]]},"reference":[{"issue":"9","key":"e_1_2_10_2_1","first-page":"117","article-title":"Arterial cardiovascular events and mortality following venous thromboembolism","volume":"3","author":"Adelborg K","year":"2015","journal-title":"Ann Transl Med"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.951236"},{"key":"e_1_2_10_4_1","first-page":"465","article-title":"How we treat bleeding associated with direct oral anticoagulants","volume":"14","author":"Marano G","year":"2016","journal-title":"Blood Transfusion = Trasfusione del Sangue"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-02-270918"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-09-199182"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2014.1.52"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.119.026545"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2009.03414.x"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2005.01236.x"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2006.02093.x"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1405760"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.20687"},{"issue":"1","key":"e_1_2_10_14_1","first-page":"83","article-title":"Preclinical Pharmacology of BAY 2433334, a Small Molecule Inhibitor of Coagulation Factor XIa [abstract]","volume":"4","author":"Heitmeier S","year":"2020","journal-title":"Res Pract Thromb Haemost"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13882"},{"key":"e_1_2_10_16_1","unstructured":"Guideline on the investigation of drug interactions. 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