{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:58:01Z","timestamp":1790927881380,"version":"4.1.0"},"reference-count":27,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:p>Pediatric extrapolation enables the application of adult efficacy data to pediatric populations when sufficient similarity is established in disease pathophysiology, pharmacologic response, and drug exposure. When these conditions are met, extrapolation can reduce or eliminate the need for dedicated pediatric efficacy trials, facilitating more efficient pediatric drug development. In this paper, we examined US Food and Drug Administration (FDA) pediatric drug approvals in neurology, analgesia, and psychiatry from 2014 to 2025 that utilized exposure matching to support extrapolation approaches. We identified 33 unique drug products that successfully implemented pharmacokinetic\u2010based exposure matching strategies across neuropsychiatric indications. Population pharmacokinetic modeling emerged as the predominant strategy for pediatric dose optimization, incorporating developmental considerations such as allometric scaling and enzyme maturation functions. FDA General Advice Letters proved instrumental in facilitating adoption of complete pediatric extrapolation approaches, demonstrating the critical role of regulatory guidance in expediting pediatric drug development. Case examples spanned broad age ranges, from mechanistically informed neonatal applications utilizing enzyme maturation modeling (risdiplam) to adolescent populations where adult dosing regimens proved adequate (brexanolone, nipocalimab). Additionally, pharmacodynamic biomarkers were pivotal in pediatric extrapolation of eculizumab and nipocalimab efficacy for the treatment of generalized myasthenia gravis, highlighting promising future directions for the field. These cases demonstrate how achieving comparable pharmacokinetics and, when necessary, pharmacodynamics profiles between adult and pediatric populations can support efficient regulatory approval without dedicated pediatric efficacy studies. The regulatory pathways established for select neuropsychiatric indications provide a compelling framework for expanding extrapolation approaches to other therapeutic areas.<\/jats:p>","DOI":"10.1002\/cpt.70412","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T06:27:05Z","timestamp":1785479225000},"page":"890-913","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pediatric Extrapolation in Neuropsychiatric Drug Development: Leveraging Pharmacokinetic and Pharmacodynamic Strategies to Facilitate\n                    <scp>FDA<\/scp>\n                    Approvals"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2191-2589","authenticated-orcid":false,"given":"Anantha Ram","family":"Nookala","sequence":"first","affiliation":[{"name":"Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food &amp; Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food &amp; Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nimishraj","family":"Panse","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food &amp; Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Bewernitz","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food &amp; Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atul","family":"Bhattaram","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food &amp; Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poonam","family":"Delvadia","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food &amp; Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2552-9536","authenticated-orcid":false,"given":"Venkateswaran C.","family":"Pillai","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food &amp; Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deep","family":"Kwatra","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food &amp; Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Xu","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food &amp; Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramana","family":"Uppoor","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food &amp; Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehul","family":"Mehta","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food &amp; Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sreedharan","family":"Sabarinath","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food &amp; Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5654-5345","authenticated-orcid":false,"given":"Gopichand","family":"Gottipati","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food &amp; Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-025-03923-3"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2010-3487"},{"key":"e_1_2_9_3_1","unstructured":"59 Specific requirements on content and format of labeling for human prescription drugs; revision of \u2018Pediatric Use\u2019 subsection in the labeling; final rule. (Federal Register)(1994)."},{"key":"e_1_2_9_4_1","unstructured":"Pediatric Research Equity Act of 2003Pub. L. No. 108\u2010155 (2003). <https:\/\/www.congress.gov\/bill\/108th\u2010congress\/senate\u2010bill\/650>. Accessed July 31 2025."},{"key":"e_1_2_9_5_1","unstructured":"Food and Drug Administration Modernization Act of 1997Pub. L. No. 105\u2010115 111 Stat. 2296 (1997). <https:\/\/www.congress.gov\/bill\/105th\u2010congress\/senate\u2010bill\/830>. Accessed July 31 2025."},{"key":"e_1_2_9_6_1","unstructured":"Best Pharmaceuticals for Children ActPub. L. No. 107\u2010109 (2002). <https:\/\/www.congress.gov\/bill\/107th\u2010congress\/senate\u2010bill\/1789?q=%7B%22search%22%3A%22BEST+PHARMACEUTICALS+FOR+CHILDREN+ACT%22%7D&s=1&r=4>. Accessed July 31 2025."},{"key":"e_1_2_9_7_1","unstructured":"Food and Drug Administration Amendments Act of 2007Pub. L. No. 110\u201085 (2007. <https:\/\/www.congress.gov\/bill\/110th\u2010congress\/house\u2010bill\/3580>). Accessed July 31 2025."},{"key":"e_1_2_9_8_1","unstructured":"General Clinical Pharmacology Considerations for Pediatric Studies of Drugs Including Biological Products(2022)."},{"key":"e_1_2_9_9_1","unstructured":"E11A Pediatric Extrapolation(2024)."},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2160"},{"key":"e_1_2_9_11_1","first-page":"1","article-title":"Extrapolation of efficacy in pediatric drug development and evidence\u2010based medicine: Progress and lessons learned","volume":"2017","author":"Sun H.","year":"2017","journal-title":"Ther. Innov. Regul. Sci."},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2681"},{"key":"e_1_2_9_13_1","unstructured":"Drugs for the Treatment of Partial Onset Seizures: Extrapolation of Efficacy from Adults to Pediatric Patients 1 Month of Age and Older(2024)."},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1836"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2010-3591"},{"key":"e_1_2_9_16_1","unstructured":"Drugs@FDA<https:\/\/www.accessdata.fda.gov\/scripts\/cder\/daf\/index.cfm>. Accessed August 22 2025."},{"key":"e_1_2_9_17_1","unstructured":"Lacosamide Clinical Pharmacology Biopharmaceutics Review(s)<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2008\/022253s000_022254s000_ClinPharmR_P1.pdf>. Accessed 11\/20\/2025."},{"key":"e_1_2_9_18_1","unstructured":"Risdiplam Clinical Pharmacology and Biopharmaceutics Review(s)<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2008\/022253s000_022254s000_MedR_P1.pdf>. Accessed 11\/20\/2025."},{"key":"e_1_2_9_19_1","unstructured":"Bupivacaine Clinical Pharmacology Biopharmaceutics Review(s)<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2011\/022496Orig1s000ClinPharmR.pdf>. Accessed 11\/20\/2025."},{"key":"e_1_2_9_20_1","unstructured":"Oxycodone Hydrochloride Clinical Pharmacology Biopharmaceutics Review(s)<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2010\/022272s000ClinPharmR.pdf>. Accessed 11\/20\/2025."},{"key":"e_1_2_9_21_1","unstructured":"Brexanolone Multi\u2010Discipline Review<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2019\/211371Orig1s000MultidisciplineR.pdf>. Accessed 11\/20\/2025."},{"key":"e_1_2_9_22_1","unstructured":"Escitalopram Clinical Pharmacology Biopharmaceutics Review(s)<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2002\/21\u2010323.pdf_Lexapro_BioPharmr.pdf>. Accessed 11\/20\/2025."},{"key":"e_1_2_9_23_1","unstructured":"Eculizumab Clinical Pharmacology Biopharmaceutics Review(s)<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2007\/125166s0000_ClinPharmR.pdf>. Accessed 11\/20\/2025."},{"key":"e_1_2_9_24_1","unstructured":"Nipocalimab Integrated Review<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2025\/761430Orig1s000IntegratedR.pdf>. Accessed 11\/20\/2025."},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2023.1119294"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.4061\/2011\/404101"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.834212"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70412","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70412","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70412","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:50:42Z","timestamp":1790927442000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70412"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":27,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/cpt.70412"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70412","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]},"assertion":[{"value":"2025-12-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}