{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T17:24:31Z","timestamp":1773422671755,"version":"3.50.1"},"reference-count":31,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2015,9,30]],"date-time":"2015-09-30T00:00:00Z","timestamp":1443571200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>This study characterized the population pharmacokinetics of edoxaban in patients with symptomatic deep\u2010vein thrombosis and\/or pulmonary embolism in the Hokusai\u2010VTE phase 3 study. The impact of the protocol\u2010specified 50% dose reductions applied to patients with body weight\u00a0\u2264\u00a060\u00a0kg, creatinine clearance (CL<jats:sub>cr<\/jats:sub>) of 30 to 50\u00a0ml min<jats:sup>\u20131<\/jats:sup> or concomitant P\u2010glycoprotein inhibitor on edoxaban exposure was assessed using simulations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The sparse data from Hokusai\u2010VTE, 9531 concentrations collected from 3707 patients, were pooled with data from 13 phase 1 studies. In the analysis, the covariate relationships used for dose reductions were estimated and differences between healthy subjects and patients as well as additional covariate effects of age, race and gender were explored based on statistical and clinical significance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A linear two\u2010compartment model with first order absorption preceded by a lag time best described the data. Allometrically scaled body weight was included on disposition parameters. Apparent clearance was parameterized as non\u2010renal and renal. The latter increased non\u2010linearly with increasing CL<jats:sub>cr<\/jats:sub>. Compared with healthy volunteers, inter\u2010compartmental clearance and the CL<jats:sub>cr<\/jats:sub> covariate effect were different in patients (+64.6% and +274%). Asian patients had a 22.6% increased apparent central volume of distribution. The effect of co\u2010administration of P\u2010glycoprotein inhibitors seen in phase 1 could not be confirmed in the phase 3 data. Model\u2010based simulations revealed lower exposure in dose\u2010reduced compared with non\u2010dose\u2010reduced patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The adopted dose\u2010reduction strategy resulted in reduced exposure compared with non\u2010dose\u2010reduced, thereby overcompensating for covariate effects. The clinical impact of these differences on safety and efficacy remains to be evaluated.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.12727","type":"journal-article","created":{"date-parts":[[2015,7,27]],"date-time":"2015-07-27T10:57:39Z","timestamp":1437994659000},"page":"1374-1387","source":"Crossref","is-referenced-by-count":23,"title":["Population pharmacokinetics of edoxaban in patients with symptomatic deep\u2010vein thrombosis and\/or pulmonary embolism\u2014the Hokusai\u2010VTE phase 3 study"],"prefix":"10.1111","volume":"80","author":[{"given":"Ronald","family":"Niebecker","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Biosciences, Uppsala University  Uppsala Sweden and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siv","family":"J\u00f6nsson","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences, Uppsala University  Uppsala Sweden and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mats O.","family":"Karlsson","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences, Uppsala University  Uppsala Sweden and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raymond","family":"Miller","sequence":"additional","affiliation":[{"name":"Modelling and Simulation, Translational Medicine and Clinical Pharmacology Daiichi Sankyo Pharma Development  Edison New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joakim","family":"Nyberg","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences, Uppsala University  Uppsala Sweden and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elke H. 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