{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T17:21:57Z","timestamp":1778001717197,"version":"3.51.4"},"reference-count":20,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T00:00:00Z","timestamp":1678147200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In the 10\u2010week, phase 2 CLARITY study of patients with major depressive disorder, adjunctive therapy to antidepressants with pimavanserin 34\u00a0mg once daily statistically significantly improved the Hamilton Depression Rating Scale (HAMD\u201017) total score (primary endpoint) and Sheehan Disability Scale (SDS) score (secondary endpoint) versus placebo. This analysis characterized the exposure\u2013response (E\u2013R) relationships of pimavanserin in this CLARITY patient population. Exposure measures were estimated for each patient based on population\u2010pharmacokinetic empirical Bayesian estimates. E\u2013R models were developed to describe exposure\u2013efficacy (HAMD\u201017, SDS, and Clinical Global Impression\u2010Improvement [CGI\u2010I] scale) and exposure\u2013safety\u00a0relationships (Karolinska Sleepiness Scale [KSS], Massachusetts General Hospital Sexual Functioning Inventory [MGH\u2010SFI], and adverse events [AEs] of headache, sedation, and somnolence) relationships. For the primary efficacy endpoint (HAMD\u201017 scores), a sigmoid maximum\u2010effect model described the time course of response, and a linear function of pimavanserin exposure was statistically significant. HAMD\u201017 scores decreased steadily over time following placebo and pimavanserin treatment; separation from placebo increased as peak pimavanserin plasma concentration (C<jats:sub>max<\/jats:sub>) increased. At median pimavanserin C<jats:sub>max<\/jats:sub> (34\u2010mg dose), the reduction from baseline in HAMD\u201017 scores was \u221211.1 and \u221213.5 at weeks 5 and 10, respectively. Relative to placebo, the model predicted comparable reductions in HAMD\u201017 scores at weeks 5 and 10. Similar improvements in favor of pimavanserin were detected with SDS, CGI\u2010I, MGH\u2010SFI, and KSS scores. No E\u2013R relationship was found for AEs. E\u2013R modeling predicted a relationship between higher pimavanserin exposure and improvement in HAMD\u201017 score and improvement across multiple secondary efficacy endpoints.<\/jats:p>","DOI":"10.1002\/cpdd.1232","type":"journal-article","created":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T08:43:22Z","timestamp":1678178602000},"page":"463-474","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exposure\u2013response Modeling From the CLARITY Trial of Pimavanserin for Adjunctive Treatment of Major Depressive Disorder"],"prefix":"10.1002","volume":"12","author":[{"given":"Mona","family":"Darwish","sequence":"first","affiliation":[{"name":"Acadia Pharmaceuticals Inc.  Princeton New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryan","family":"Dirks","sequence":"additional","affiliation":[{"name":"Acadia Pharmaceuticals Inc.  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