{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T10:52:13Z","timestamp":1783075933976,"version":"3.54.6"},"reference-count":31,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,3,21]],"date-time":"2019-03-21T00:00:00Z","timestamp":1553126400000},"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":[[2019,5]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Agomelatine is an antidepressant for major depressive disorders. It undergoes extensive first\u2010pass hepatic metabolism and displays irregular absorption profiles and large interindividual variability (IIV) and interoccasion variability of pharmacokinetics. The objective of this study was to characterize the complex pharmacokinetics of agomelatine and its metabolites in healthy subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Plasma concentration\u2013time data of agomelatine and its metabolites were collected from a 4\u2010period, cross\u2010over bioequivalence study, in which 44 healthy subjects received 25\u00a0mg agomelatine tablets orally. Nonlinear mixed effects modelling was used to characterize the pharmacokinetics and variability of agomelatine and its metabolites. Deterministic simulations were carried out to investigate the influence of pathological changes due to liver disease on agomelatine pharmacokinetics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A semiphysiological pharmacokinetic model with parallel first\u2010order absorption and a well\u2010stirred liver compartment adequately described the data. The estimated IIV and interoccasion variability of the intrinsic clearance of agomelatine were 130.8% and 28.5%, respectively. The IIV of the intrinsic clearance turned out to be the main cause of the variability of area under the curve\u2010based agomelatine exposure. Simulations demonstrated that a reduction in intrinsic clearance or liver blood flow, and an increase in free drug fraction had a rather modest influence on agomelatine exposures (range: \u221250 to 200%). Portosystemic shunting, however, substantially elevated agomelatine exposure by 12.6\u2013109.1\u2010fold.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A semiphysiological pharmacokinetic model incorporating first\u2010pass hepatic extraction was developed for agomelatine and its main metabolites. The portosystemic shunting associated with liver disease might lead to significant alterations of agomelatine pharmacokinetics, and lead to substantially increased exposure.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.13902","type":"journal-article","created":{"date-parts":[[2019,2,14]],"date-time":"2019-02-14T09:05:38Z","timestamp":1550135138000},"page":"1003-1014","source":"Crossref","is-referenced-by-count":8,"title":["A semiphysiological population pharmacokinetic model of agomelatine and its metabolites in Chinese healthy volunteers"],"prefix":"10.1111","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8427-4030","authenticated-orcid":false,"given":"Feifan","family":"Xie","sequence":"first","affiliation":[{"name":"Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences Ghent University  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences Ghent University  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3616-5539","authenticated-orcid":false,"given":"Pieter","family":"Colin","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences Ghent University  Ghent Belgium"},{"name":"Department of Anesthesiology University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9352-9744","authenticated-orcid":false,"given":"Zeneng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Research Institute of Drug Metabolism and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,3,21]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.5455\/jeim.100511.ir.005"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2014.862233"},{"key":"e_1_2_9_4_1","first-page":"10","article-title":"Agomelatine: a novel antidepressant","volume":"8","author":"Sansone RA","year":"2011","journal-title":"Innov Clin Neurosci"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.2147\/CE.S6005"},{"key":"e_1_2_9_6_1","unstructured":"TGA.Gov.au.Australian Public Assessment Report for Agomelatine 2010.https:\/\/www.tga.gov.au\/sites\/default\/files\/auspar\u2010valdoxan.pdf. 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