{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:10:17Z","timestamp":1791277817344,"version":"4.1.0"},"reference-count":34,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2013,10,21]],"date-time":"2013-10-21T00:00:00Z","timestamp":1382313600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Bristol-Myers Squibb"},{"name":"Pfizer Inc"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2013,11]]},"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>Apixaban is an oral factor<jats:styled-content style=\"fixed-case\">X<\/jats:styled-content>a inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>This double\u2010blind, randomized, placebo\u2010controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels \u2013 apixaban 2.5, 5, 10 and 25\u2009mg twice daily and 10 and 25\u2009mg once daily\u2013 with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (<jats:styled-content style=\"fixed-case\">AEs<\/jats:styled-content>). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (<jats:styled-content style=\"fixed-case\">INR<\/jats:styled-content>), activated partial thromboplastin time (<jats:styled-content style=\"fixed-case\">aPTT<\/jats:styled-content>) and modified prothrombin time (<jats:styled-content style=\"fixed-case\">mPT<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Forty\u2010eight subjects were randomized and treated (apixaban,<jats:italic>n<\/jats:italic>= 36; placebo,<jats:italic>n<\/jats:italic>= 12); one subject receiving 2.5\u2009mg twice daily discontinued due to<jats:styled-content style=\"fixed-case\">AEs<\/jats:styled-content>(headache and nausea). No dose limiting<jats:styled-content style=\"fixed-case\">AEs<\/jats:styled-content>were observed. Apixaban maximum plasma concentration was achieved \u223c3\u2009h post\u2010dose. Exposure increased approximately in proportion to dose. Apixaban steady\u2010state concentrations were reached by day 3, with an accumulation index of 1.3\u20131.9. Peak\u2009:\u2009trough ratios were lower for twice daily<jats:italic>vs.<\/jats:italic>once daily regimens. Clotting times showed dose\u2010related increases tracking the plasma concentration\u2013time profile.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Multiple oral doses of apixaban were safe and well tolerated over a 10\u2010fold dose range, with pharmacokinetics with low variability and concentration\u2010related increases in clotting time measures.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.12106","type":"journal-article","created":{"date-parts":[[2013,3,5]],"date-time":"2013-03-05T06:00:11Z","timestamp":1362463211000},"page":"776-786","source":"Crossref","is-referenced-by-count":257,"title":["Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor<scp>X<\/scp>a inhibitor, in healthy subjects"],"prefix":"10.1111","volume":"76","author":[{"given":"Charles","family":"Frost","sequence":"first","affiliation":[{"name":"Bristol\u2010Myers Squibb Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil","family":"Nepal","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessie","family":"Wang","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Schuster","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonkyung","family":"Byon","sequence":"additional","affiliation":[{"name":"Pfizer Inc Groton CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca A.","family":"Boyd","sequence":"additional","affiliation":[{"name":"Pfizer Inc Groton CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Yu","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Shenker","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Chen","family":"Barrett","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rogelio","family":"Mosqueda\u2010Garcia","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"LaCreta","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,10,21]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.11-2301"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1592\/phco.24.10.62S.36120"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1055\/s-0038-1665430","article-title":"Thrombotic events during oral anticoagulant treatment: results of the inception\u2010cohort, prospective, collaborative ISCOAT study: ISCOAT study group (Italian Study on Complications of Oral Anticoagulant Therapy)","volume":"78","author":"Palareti G","year":"1997","journal-title":"Thromb Haemost"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm0109513"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-002-8415-9"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm070245n"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm050101d"},{"key":"e_1_2_9_9_1","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0022-3565(24)35299-1","article-title":"Nonpeptide factor Xa inhibitors: I. 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