{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T04:45:32Z","timestamp":1788929132197,"version":"build-2803163510"},"reference-count":20,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2018,6,7]],"date-time":"2018-06-07T00:00:00Z","timestamp":1528329600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Daiichi Sankyo Co., Ltd."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>To characterize the pharmacokinetics, pharmacodynamics and safety of esaxerenone, a mineralocorticoid receptor antagonist, in healthy adult Japanese men.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Double\u2010blind, placebo\u2010controlled, sequential, dose\u2010escalation studies were conducted in subjects randomized to receive oral once\u2010daily esaxerenone (ranges: 5\u2013200\u00a0mg [single\u2010dose]; 10\u2013100\u00a0mg over 10\u00a0days [multiple\u2010dose]) or placebo under fasting conditions. Plasma concentrations were analysed by liquid chromatograph\u2013tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartment analysis. Plasma\/urine levels of pharmacodynamic biomarkers for mineralocorticoid receptor activity were evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In total, 48\/48 and 39\/40 subjects completed the single\u2010 and multiple\u2010dose studies, respectively. Exposures were generally dose\u2010proportional. The t<jats:sub>max<\/jats:sub>, t<jats:sub>1\/2<\/jats:sub> and CL\/F remained unchanged, independent of dose; the respective ranges were 1.5\u20134.0\u00a0h, 22.3\u201325.1\u00a0h, and 4.0\u20135.2\u00a0l\u00a0h<jats:sup>\u20131<\/jats:sup> (multiple\u2010dose study). V<jats:sub>z<\/jats:sub>\/F ranged from 136.5 to 283.7\u00a0l in the multiple\u2010dose study, and exposure reached steady state by day 4. The mean observed accumulation ratio, by dose, ranged from 1.36\u20131.98. The urinary Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup> ratio increased after single\u2010dose administration; however, its relationship to the doses tested remains unclear. Plasma renin activity, active renin concentration and aldosterone concentration increased dose\u2010dependently. Although blood potassium levels increased dose\u2010dependently in the multiple\u2010dose study (reaching a maximum mean\u00a0\u00b1\u00a0standard deviation of 4.63\u00a0\u00b1\u00a00.354\u00a0mmol\u00a0l<jats:sup>\u20131<\/jats:sup> in the 100\u2010mg group), no safety\/tolerability\u2010related problems were detected in either study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Exposure levels in healthy adults receiving esaxerenone were generally dose\u2010proportional. Dose\u2010dependent changes in plasma pharmacodynamic biomarkers for the mineralocorticoid receptor were identified during multiple\u2010dose treatment and support the pharmacological activity of esaxerenone. No important safety concerns were identified.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.13616","type":"journal-article","created":{"date-parts":[[2018,4,24]],"date-time":"2018-04-24T13:36:24Z","timestamp":1524576984000},"page":"1821-1829","source":"Crossref","is-referenced-by-count":47,"title":["Single\u2010 and multiple\u2010dose escalation study to assess pharmacokinetics, pharmacodynamics and safety of oral esaxerenone in healthy Japanese subjects"],"prefix":"10.1111","volume":"84","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3790-2804","authenticated-orcid":false,"given":"Manabu","family":"Kato","sequence":"first","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetoshi","family":"Furuie","sequence":"additional","affiliation":[{"name":"Osaka Pharmacology Clinical Research Hospital  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takako","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuhiro","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiaki","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo, Inc.  New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Ishizuka","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,6,7]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/hr.2014.20"},{"key":"e_1_2_8_3_1","unstructured":"Health Service Bureau Ministry of Health Labour and Welfare.Outline for the results of the National Health and Nutrition Survey Japan 2006. Tokyo: Ministry of Health Labour and Welfare 2008. 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