{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:03:23Z","timestamp":1792623803729,"version":"4.5.0"},"reference-count":24,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"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":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Anaphylaxis is a rapid, potentially fatal allergic reaction with a global prevalence of 0.04%\u20101.8%. Early intramuscular epinephrine administration is recommended. However, fear, pain, cost, or social barriers often delay treatment, leading to poor outcomes. To address these challenges, an intranasal (IN) epinephrine formulation was developed. Pharmacokinetic (PK) data for IN epinephrine are absent in children &lt;4\u00a0years (7.5\u201015\u00a0kg) and limited in children \u22654\u00a0years. To inform pediatric dosing, we developed a population PK model to support weight\u2010based dosing (\u226530\u00a0kg, 15\u2010&lt;30\u00a0kg, and 7.5\u2010&lt;15\u00a0kg) in children. Pooled single\u2010dose IN epinephrine data from six studies (five adults, one pediatric), with 255 subjects and 3564 observations, were analyzed using nonlinear mixed\u2010effects modeling (NONMEM v7.5). Data handling included baseline imputation, exclusion of endogenous concentrations (&gt;4\u00a0h), and BLQ management via the M4 method. One\u2010 and two\u2010compartment models with allometric scaling by body weight were evaluated. Model performance was assessed using diagnostic plots, objective function value, and prediction\u2010corrected visual predictive checks (pcVPC). Pediatric exposure simulations used CDC\u2010based virtual populations to guide weight\u2010based dosing. A two\u2010compartment model with first\u2010order absorption best described the data, with acceptable relative standard error &lt;30% and no evidence of model misspecification. pcVPC demonstrated good agreement across adult and pediatric subgroups. Simulations indicated that the pediatric doses of 2\u00a0mg (\u226530\u00a0kg) and 1\u00a0mg (15\u2010&lt;30\u00a0kg) achieved exposure comparable to the adult 2\u00a0mg reference, supporting the dosing strategy. Model\u2010informed simulations support weight\u2010based IN epinephrine dosing in young children, addressing a critical gap in anaphylaxis management.<\/jats:p>","DOI":"10.1002\/jcph.70294","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:02:07Z","timestamp":1788948127000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Model\u2010Informed Dose Selection of Intranasal Epinephrine in Young Children"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6365-8411","authenticated-orcid":false,"given":"Manav","family":"Jain","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida  Orlando FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2805-7960","authenticated-orcid":false,"given":"Priscila A","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida  Orlando FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9175-5702","authenticated-orcid":false,"given":"Amira","family":"Soliman","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida  Orlando FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Lowenthal","sequence":"additional","affiliation":[{"name":"ARS Pharmaceuticals  San Diego CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2636-1889","authenticated-orcid":false,"given":"Valvanera","family":"Vozmediano","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida  Orlando FL USA"},{"name":"Model Informed Development Regulatory Development and Consulting CTI Laboratories  Covington KY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4998-1167","authenticated-orcid":false,"given":"Stephan","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida  Orlando FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4389-058X","authenticated-orcid":false,"given":"Natalia","family":"de Moraes","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida  Orlando FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.5114\/ada.2021.103327"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2021.01.010"},{"key":"e_1_2_10_4_1","unstructured":"DalalR GrujicD.Epinephrine. StatPearls Publishing; 2024.https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK482160\/"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2023.09.015"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/pec.0000000000002783"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/aci.0000000000001109"},{"key":"e_1_2_10_8_1","unstructured":"US Food and Drug Administration. Highlights of prescribing information: Neffy (epinephrine nasal spray). FDA prescribing information. Revised August 2024. Accessed May 19 2026.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2024\/214697s000lbl.pdf"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2023.11.006"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2022.10.024"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics16060811"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.08.007"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2025.03.019"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1478"},{"key":"e_1_2_10_15_1","unstructured":"US Food and Drug Administration. E11A Pediatric Extrapolation Guidance for Industry. Published December 2024. 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