{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T08:11:36Z","timestamp":1758874296840,"version":"3.37.3"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T00:00:00Z","timestamp":1644451200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T00:00:00Z","timestamp":1644451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Pharmacol Toxicol"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Digoxin is an important treatment option for reducing the ventricular rate in patients with atrial fibrillation (AF) and heart failure (HF). Digoxin has a narrow therapeutic window and large interindividual variability. A low target blood concentration, especially \u22640.9\u2009ng\/mL, is recommended for patients with HF who are taking digoxin. This study aimed to develop a population pharmacokinetic model and to identify clinical factors that affect digoxin exposure and an optimal digoxin dosing regimen in Japanese patients with AF and HF.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>A population pharmacokinetic analysis was performed by using a nonlinear mixed effects model based on 3465 concentration points from 391 patients (&gt;18\u2009years) who were receiving oral digoxin. Using trough serum digoxin concentrations and clinical data, a population pharmacokinetic model was developed for determining covariates of clearance. A 1-compartment model was used to examine the interindividual variability of the oral clearance (CL\/F) of digoxin. An appropriate dosage of digoxin was identified using Monte Carlo simulation.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The final model demonstrated that creatinine clearance (CL<jats:sub>CR<\/jats:sub>) and the use of amiodarone were factors that contributed to the CL\/F of digoxin. Monte Carlo simulation results showed that with a daily maintenance dose of 0.25\u2009mg, the intoxication risk window of a trough serum concentration of \u22650.9\u2009ng\/mL could be reached in more than half of patients regardless of renal function category or concurrent use of amiodarone. The appropriate maintenance dosage was 0.125\u2009mg daily for most Japanese patients with AF and HF. However, with a daily dose of 0.125\u2009mg, a trough serum concentration of \u22650.9\u2009ng\/mL could be reached in more than half of patients with renal impairments (CL<jats:sub>CR<\/jats:sub> 30\u2009mL\/min) or concurrent use of amiodarone. A daily maintenance dose of 0.0625\u2009mg was acceptable for these patients.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>CL<jats:sub>CR<\/jats:sub> and the use of amiodaron were found to contribute to digoxin clearance using a population pharmacokinetic methodology. For Japanese patients with AF and HF, 0.125\u2009mg is an appropriate daily digoxin maintenance dose, but a dose reduction is required for patients with CL<jats:sub>CR<\/jats:sub>\u2009&lt;30\u2009mL\/min or concurrent amiodarone use.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40360-022-00552-y","type":"journal-article","created":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T12:02:57Z","timestamp":1644494577000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Population pharmacokinetic analysis and dosage recommendations for digoxin in Japanese patients with atrial fibrillation and heart failure using real-world data"],"prefix":"10.1186","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3898-2068","authenticated-orcid":false,"given":"Toshinori","family":"Hirai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidefumi","family":"Kasai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miyoko","family":"Naganuma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuhisa","family":"Hagiwara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0358-7196","authenticated-orcid":false,"given":"Tsuyoshi","family":"Shiga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,2,10]]},"reference":[{"issue":"27","key":"552_CR1","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1093\/eurheartj\/ehw128","volume":"37","author":"P Ponikowski","year":"2016","unstructured":"Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). 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The study received ethical approval for the use of an opt-out approach to consent. The Institutional Review Boards of both sites permitted a transfer of study data from Tokyo Women\u2019s Medical University to Jikei University for collaborative research. This study was conducted in compliance with Ethical Guidelines for Medical and Biological Research Involving Human Subjects issued by the Japanese Ministry of Health, Labour and Welfare and the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors have no potential conflicts of interest to declare.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"14"}}