{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T05:03:37Z","timestamp":1784955817047,"version":"3.55.0"},"reference-count":23,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The US FDA recently accepted efficacy extrapolation from adult to pediatric patients for atypical antipsychotics in the treatment of schizophrenia (SCZ) and bipolar mania (BPM), considering the similarity in both disease and exposure\u2010response relationships for this class of drugs. Under this pharmacokinetic (PK)\u2010based efficacy extrapolation framework, pediatric population PK (popPK) models for cariprazine and its two active metabolites (desmethyl cariprazine [DCAR], didesmethyl cariprazine [DDCAR]) were developed by modifying previously validated adult popPK models and using pediatric PK data from two phase I trials. Covariate effects on PK parameters in legacy adult models were retained in the pediatric models, except that body weight effect on apparent elimination clearance and apparent volume of distribution of the central compartment were re\u2010estimated for all analytes. The final pediatric popPK models adequately described observed plasma concentrations of all three analytes with no significant bias over age or body weight in pediatric patients. Simulated total cariprazine (sum of cariprazine, DCAR and DDCAR) exposure at 1.5\u20104.5\u00a0mg once daily (QD) in adolescents (13\u201017\u00a0years) with SCZ and 3.0\u20104.5\u00a0mg QD in children (10\u201012\u00a0years) and adolescents with BPM resulted in predicted total cariprazine exposures within established efficacious ranges in adults with these conditions. Body weight did not meaningfully affect total cariprazine exposure and analyses did not support weight\u2010based dosing in 10\u201012 year olds. This PK analysis supported the FDA approvals of cariprazine for the treatment of SCZ and BPM in pediatric patients by identifying efficacious doses for each indication based on efficacy extrapolation.<\/jats:p>","DOI":"10.1002\/jcph.70243","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T08:40:53Z","timestamp":1784104853000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Extrapolating Efficacy of Cariprazine to Pediatric Schizophrenia and Bipolar Mania Through Population Pharmacokinetic Analysis"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6289-703X","authenticated-orcid":false,"given":"Shams","family":"Ismaeil","sequence":"first","affiliation":[{"name":"Clinical Pharmacology AbbVie Inc.  North Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6003-7027","authenticated-orcid":false,"given":"Lucia","family":"Siovitz","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Deutschland GmbH Co. KG  Ludwigshafen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2648-6649","authenticated-orcid":false,"given":"Rahul K.","family":"Goyal","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Inc.  North Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5946-2364","authenticated-orcid":false,"given":"Doerthe","family":"Eckert","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Deutschland GmbH Co. KG  Ludwigshafen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7986-4447","authenticated-orcid":false,"given":"Sven","family":"Stodtmann","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Deutschland GmbH Co. KG  Ludwigshafen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8245-0904","authenticated-orcid":false,"given":"Hao","family":"Xiong","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Inc.  North Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"Schizophrenia.National Institute of Mental Health. Accessed October 29 2025.https:\/\/www.nimh.nih.gov\/health\/statistics\/schizophrenia#part_2544"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00406\u2010025\u201002169\u20108"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380\u2010021\u201001161\u20107"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40272\u2010024\u201000669\u2010z"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2024.02.005"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2009.1549"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.2147\/dddt.s188760"},{"key":"e_1_2_11_9_1","unstructured":"VRAYLAR (cariprazine) [package insert].AbbVie Inc.2025. Accessed January 15 2026.https:\/\/www.rxabbvie.com\/pdf\/vraylar_pi.pdf"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1089\/cap.2021.0139"},{"key":"e_1_2_11_11_1","unstructured":"E11A pediatric extrapolation: guidance for industry.US Food and Drug Administration.2024. Accessed October 29 2025.https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/e11a\u2010pediatric\u2010extrapolation"},{"key":"e_1_2_11_12_1","unstructured":"ICH E11(R1) guideline on clinical investigation of medicinal products in the pediatric population \u2010 Revision 1 (addendum).European Medicines Agency.2017. Accessed 28 October 28 2025.https:\/\/www.ema.europa.eu\/en\/ich\u2010e11r1\u2010guideline\u2010clinical\u2010investigation\u2010medicinal\u2010products\u2010pediatric\u2010population\u2010scientific\u2010guideline"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1580"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1501"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1836"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318\u2010020\u201000650\u20104"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.2147\/dddt.s95100"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12720"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010008\u20109094\u20104"},{"key":"e_1_2_11_20_1","unstructured":"CDC growth charts.US Centers for Disease Control and Prevention.2024. Accessed October 31 2025.http:\/\/www.cdc.gov\/growthcharts\/clinical_charts.htm"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaac.2025.08.069"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2429"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2307"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010016\u20100436\u2010x"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.70243","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcph.70243","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.70243","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T04:46:28Z","timestamp":1784954788000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.70243"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7]]},"references-count":23,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1002\/jcph.70243"],"URL":"https:\/\/doi.org\/10.1002\/jcph.70243","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7]]},"assertion":[{"value":"2026-04-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70243"}}