{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T10:51:33Z","timestamp":1783075893089,"version":"3.54.6"},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,12,8]],"date-time":"2015-12-08T00:00:00Z","timestamp":1449532800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007723","name":"Takeda Pharmaceuticals U.S.A.","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007723","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Basic Clin Pharma Tox"],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Vortioxetine is approved for the treatment of major depressive disorder (MDD). This analysis aimed to develop pharmacokinetic (PK) and PK\/Efficacy models to evaluate the exposure\u2013response relationship for vortioxetine in patients with MDD. PK data from 10 MDD and two generalized anxiety disorder studies of vortioxetine (3160 patients), and efficacy data [Montgomery\u2013\u00c5sberg Depression Rating Scale (MADRS)] from seven MDD studies (2537 patients), were used for the development of PK and PK\/Efficacy models. One\u2010 and two\u2010compartment models were evaluated as structural PK models, and linear and nonlinear (<jats:italic>E<\/jats:italic><jats:sub>max<\/jats:sub>) models were used to describe the relationship between average vortioxetine concentration at steady\u2010state (<jats:italic>C<\/jats:italic><jats:sub>av<\/jats:sub>) and change in MADRS score from baseline (\u0394MADRS). The impact of selected covariates on the PK and efficacy parameters of vortioxetine was also investigated. PK of vortioxetine was best characterized by a two\u2010compartment model with first\u2010order absorption and elimination. Mean estimates for oral clearance (CL\/<jats:italic>F<\/jats:italic>) and volume of distribution for the central compartment of vortioxetine were 42\u00a0L\/hr and 2920\u00a0L. Creatinine clearance, height and geographic region had statistically significant effects on vortioxetine CL\/<jats:italic>F<\/jats:italic>, but the effect of each of these covariates was not considered clinically relevant, as they lead to \u00b126% change in area under the curve or <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> of vortioxetine. An <jats:italic>E<\/jats:italic><jats:sub>max<\/jats:sub> model best described the relationship between \u0394MADRS and <jats:italic>C<\/jats:italic><jats:sub>av<\/jats:sub>. Half\u2010maximal effective concentration (EC<jats:sub>50<\/jats:sub>) and <jats:italic>E<\/jats:italic><jats:sub>max<\/jats:sub> estimates were 24.9\u00a0ng\/mL and 7.0. No identified covariates, except region, had clinically meaningful effects on vortioxetine efficacy. These PK\/Efficacy models adequately characterized the vortioxetine exposure\u2013response relationship.<\/jats:p>","DOI":"10.1111\/bcpt.12513","type":"journal-article","created":{"date-parts":[[2015,11,3]],"date-time":"2015-11-03T05:08:40Z","timestamp":1446527320000},"page":"344-355","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A Population Pharmacokinetic\u2013Pharmacodynamic Meta\u2010Analysis of Vortioxetine in Patients with Major Depressive Disorder"],"prefix":"10.1111","volume":"118","author":[{"given":"Himanshu","family":"Naik","sequence":"first","affiliation":[{"name":"Takeda Pharmaceuticals USA Inc. Deerfield IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Chan","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceuticals USA Inc. Deerfield IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majid","family":"Vakilynejad","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceuticals USA Inc. Deerfield IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Chen","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas Inc. Deerfield IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Loft","sequence":"additional","affiliation":[{"name":"H. Lundbeck A\/S Valby Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atul R.","family":"Mahableshwarkar","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas Inc. 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October 1 2013.http:\/\/investor.lundbeck.com\/releasedetail.cfm?ReleaseID=794050(last accessed on 19 November 2014)."},{"key":"e_1_2_6_21_1","unstructured":"Lundbeck.Lundbeck receives European marketing authorization for Brintellix for the treatment of adults with Major Depressive Episodes [Lundbeck Web site]. 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