{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T03:14:33Z","timestamp":1788146073093,"version":"build-2803163510"},"reference-count":14,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":30,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;amp;D Transl Res &amp;amp; Clin Interv"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Remlifanserin, or ACP\u2010204, is a potent serotonin 2A receptor inverse agonist under investigation for treatment of Alzheimer's disease psychosis and Lewy body dementia psychosis. A population pharmacokinetics (popPK) model for remlifanserin was developed to evaluate the impact of covariates affecting pharmacokinetic variability and assess the clinical relevance of these factors in a virtual population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      A popPK model was developed using remlifanserin plasma concentrations (\n                      <jats:italic>n<\/jats:italic>\n                      = 3935) from 209 participants across seven Phase 1 trials (10 to 180 mg, oral). Data were pooled and analyzed using non\u2010linear mixed\u2010effects modeling. Intrinsic (demographics, hepatic\/renal function) and extrinsic (food effect) factors were assessed. Model evaluation included goodness\u2010of\u2010fit plots and prediction\u2010corrected visual predictive checks (pcVPCs). Interindividual variability was estimated for key parameters; residual variability was modeled using proportional error. Simulated steady\u2010state exposures (maximum plasma concentration at steady state [C\n                      <jats:sub>max,ss<\/jats:sub>\n                      ] and area under the plasma concentration\u2010time curve over the 24\u2010h dosing interval at steady state [AUC\n                      <jats:sub>0\u201324,ss<\/jats:sub>\n                      ]) in a virtual population (\n                      <jats:italic>n<\/jats:italic>\n                      = 1000; 60 mg\/day) were derived using PK parameters sampled from the final model. The clinical relevance of significant covariates was evaluated using geometric mean ratios and 90% confidence intervals (CIs) of exposures using a 0.8 to 1.25 boundary presented in a forest plot.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      The final popPK model was a one\u2010compartment model with first\u2010order absorption with lag time and linear elimination. Typical parameter estimates included apparent oral clearance (35.4 L\/h), apparent oral volume of distribution (V\/F) (male, 930 L; female, 799 L),\u00a0absorption lag time (ALAG1) (fasted, 0.720 h; fed, 0.929 h)and absorption rate constant (K\n                      <jats:sub>a<\/jats:sub>\n                      ) (0.692\/h). Goodness\u2010of\u2010fit plots and pcVPCs demonstrated that the model adequately captured the central tendency and magnitude of variability in remlifanserin concentrations. Statistically significant relationships were found between food and ALAG1 and between sex and V\/F (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.001); however, neither factor had a clinically relevant impact on C\n                      <jats:sub>max,ss<\/jats:sub>\n                      or AUC\n                      <jats:sub>0\u201324,ss<\/jats:sub>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>The pharmacokinetics of oral remlifanserin (10 to 180 mg) are well described by dose\u2010proportional linear kinetics. No intrinsic or extrinsic factors exhibited a clinically relevant effect on steady\u2010state remlifanserin exposures.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70254","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T07:11:14Z","timestamp":1777619474000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Population pharmacokinetics of remlifanserin (ACP\u2010204), a serotonin 2A receptor inverse agonist"],"prefix":"10.1002","volume":"12","author":[{"given":"Mona","family":"Darwish","sequence":"first","affiliation":[{"name":"Acadia Pharmaceuticals Inc.  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Lin","sequence":"additional","affiliation":[{"name":"Simulations Plus Inc., Research Triangle Park  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Dirks","sequence":"additional","affiliation":[{"name":"Acadia Pharmaceuticals Inc.  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Jaworowicz","sequence":"additional","affiliation":[{"name":"Simulations Plus Inc., Research Triangle Park  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Maxwell","sequence":"additional","affiliation":[{"name":"Simulations Plus Inc., Research Triangle Park  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjeev","family":"Pathak","sequence":"additional","affiliation":[{"name":"Acadia Pharmaceuticals Inc.  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-231363"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2018.29"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2034634"},{"key":"e_1_2_9_5_1","unstructured":"Acadia Pharmaceuticals Inc.NUPLAZID\u00ae (pimavanserin) Prescribing Information Full Prescribing Information. San Diego California:2025."},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)62106-6"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30039-5"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2022.892199"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0000000000001611"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2010.02.337"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.11.0304"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9255-z"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.149"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1026451721686"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2022.1133"}],"container-title":["Alzheimer's &amp; Dementia: Translational Research &amp; Clinical Interventions"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/trc2.70254","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/trc2.70254","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/trc2.70254","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T02:47:44Z","timestamp":1788144464000},"score":1,"resource":{"primary":{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/10.1002\/trc2.70254"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4]]},"references-count":14,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/trc2.70254"],"URL":"https:\/\/doi.org\/10.1002\/trc2.70254","archive":["Portico"],"relation":{},"ISSN":["2352-8737","2352-8737"],"issn-type":[{"value":"2352-8737","type":"print"},{"value":"2352-8737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4]]},"assertion":[{"value":"2025-12-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70254"}}