{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:08:21Z","timestamp":1790878101293,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,4,27]],"date-time":"2025-04-27T00:00:00Z","timestamp":1745712000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>To evaluate the effects of amiodarone and\/or N\u2010desethylamiodarone concentrations on digoxin pharmacokinetics and determine the optimal dose of digoxin combined with amiodarone in Japanese patients with atrial fibrillation and heart failure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A population pharmacokinetic analysis of 3288 points from 368 patients receiving oral digoxin, including 48 (13%) who were coadministered amiodarone, was performed. A 1\u2010compartment model with first\u2010order absorption with amiodarone or N\u2010desethylamiodarone as time\u2010varying covariates for apparent digoxin clearance was constructed using stepwise forward inclusion and backward elimination approaches. The percentage of patients with digoxin values in the toxic range (\u22650.9\u2009ng\/mL) was evaluated with Monte Carlo simulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The median serum digoxin concentration was 0.75\u2009ng\/mL; the median plasma concentrations of amiodarone and N\u2010desethylamiodarone were 610\u2009and 644\u2009ng\/mL, respectively. The final model for oral clearance of digoxin was explained by creatinine clearance (CLcr) and the N\u2010desethylamiodarone concentration. Digoxin clearance increased by 21% when CLcr was doubled and decreased by 3% when the N\u2010desethylamiodarone concentration increased by 100\u2009ng\/mL. In the simulation, the proportion of patients with values in the toxic range was high at 0.125\u2009mg daily among patients taking amiodarone. A daily dose of 0.0625\u2009mg is recommended for patients with a CLcr &gt;30\u2009mL\/min. For patients with a CLcr \u226430\u2009mL\/min and an N\u2010desethylamiodarone concentration &gt;600\u2009ng\/mL, a daily dose of 0.03125\u2009mg is recommended because of reduced digoxin clearance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study revealed that renal impairment and high plasma N\u2010desethylamiodarone concentrations reduce digoxin clearance in patients with atrial fibrillation and heart failure.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bcp.70075","type":"journal-article","created":{"date-parts":[[2025,4,27]],"date-time":"2025-04-27T23:40:34Z","timestamp":1745797234000},"page":"2827-2835","source":"Crossref","is-referenced-by-count":2,"title":["Population pharmacokinetic analysis of the interaction of digoxin with N\u2010desethylamiodarone in patients with atrial fibrillation and heart failure"],"prefix":"10.1002","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3898-2068","authenticated-orcid":false,"given":"Toshinori","family":"Hirai","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics The Jikei University School of Medicine  Tokyo Japan"},{"name":"Department of Pharmacy Institute of Science Tokyo Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5231-8027","authenticated-orcid":false,"given":"Hidefumi","family":"Kasai","sequence":"additional","affiliation":[{"name":"Keio University, Keio Frontier Research &amp; Education Collaborative Square (K\u2010FRECS) at Tonomachi  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0358-7196","authenticated-orcid":false,"given":"Tsuyoshi","family":"Shiga","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics The Jikei University School of Medicine  Tokyo Japan"},{"name":"Department of Cardiology Tokyo Women's Medical University  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000132482.95686.87"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-19-0342"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab368"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-197702010-00001"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt19751819"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/MEJ.0000000000001065"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.121.007955"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.298.11.1312"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40360-022-00552-y"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40780-015-0023-6"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.2165\/11532320-000000000-00000"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0928-0987(00)00215-3"},{"key":"e_1_2_10_14_1","first-page":"e240","article-title":"2013 ACCF\/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation\/American Heart Association task force on practice guidelines","volume":"128","author":"Yancy CW","year":"2013","journal-title":"Circulation"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.3999\/jscpt.51.57"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1159\/000180580"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2008.12.034"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2010.02.344"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1067\/mcp.2000.107047"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.289.7.871"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(02)01708-4"},{"issue":"2","key":"e_1_2_10_22_1","first-page":"S289","article-title":"The concise guide to PHARMACOLOGY 2023\/24: enzymes","volume":"180","author":"Alexander SPH","year":"2023","journal-title":"Br J Pharmacol"},{"issue":"2","key":"e_1_2_10_23_1","first-page":"S374","article-title":"The concise guide to PHARMACOLOGY 2023\/24: transporters","volume":"180","author":"Alexander SPH","year":"2023","journal-title":"Br J Pharmacol"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1253\/circj.66.600"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJGM.S218393"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)10423-0"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.2003.01824.x"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7015-2-8"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(85)80466-6"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(85)80091-7"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01881526"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(84)80327-7"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaa612"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-20-1212"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bcp.70075","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T07:31:01Z","timestamp":1758871861000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/bcp.70075"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,27]]},"references-count":33,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/bcp.70075"],"URL":"https:\/\/doi.org\/10.1002\/bcp.70075","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,27]]}}}