{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T21:24:40Z","timestamp":1789680280687,"version":"4.0.1"},"reference-count":34,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T00:00:00Z","timestamp":1752278400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100024157","name":"Neurelis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100024157","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Benzodiazepine immediate\u2010use seizure medications (ISMs; also called rescue therapies) are used to treat seizure clusters\/acute repetitive seizures in patients with epilepsy. In the United States, diazepam nasal spray is an approved ISM for patients \u22652\u2009years of age. The primary objective was to assess diazepam nasal spray pharmacokinetics (PK) in patients 2\u20135\u2009years of age; safety and tolerability were secondary objectives.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This Phase 1\/2a, open\u2010label, single\u2010dose, PK study with a 180\u2010day open\u2010label safety period enrolled patients with epilepsy 2\u20135\u2009years of age. Diazepam nasal spray (0.5\u2010mg\/kg per diazepam rectal gel dosing) was administered by a medical professional, followed by PK sampling. During the safety period, caregivers administered diazepam nasal spray as needed for frequent or acute repetitive seizures. Seizures and dosing were recorded in a diary. Study visits included safety evaluations. Use of second doses was a proxy for effectiveness.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Thirty\u2010six patients were enrolled, with 35 in the PK population. PK parameters and modeling were comparable to older children and adults, confirming that diazepam nasal spray was readily absorbed and supporting the adequacy of the 0.5\u2010mg\/kg dose for this age group. In the open\u2010label period, second doses within 24\u2009h of the initial dose were administered for 16.3% of seizure events (37\/227), indicating that a second dose was not used for most seizure events (83.7%). Treatment\u2010related\u00a0treatment\u2010emergent adverse events occurred in seven patients (19.4%); all were mild except one (moderate). There was one report each of respiratory depression and respiratory distress; neither was treatment related.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>This study characterizes the PK of diazepam in patients 2\u20135\u2009years of age and reports a safety profile consistent with older patients. Results demonstrate that the diazepam nasal spray drug\u2013device combination is appropriate for drug delivery and absorption in these patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.18473","type":"journal-article","created":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T14:45:22Z","timestamp":1752331522000},"page":"3231-3241","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pharmacokinetics and 180\u2010day safety of diazepam nasal spray in pediatric patients with epilepsy aged 2\u20135\u2009years"],"prefix":"10.1111","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9986-6394","authenticated-orcid":false,"given":"Eric B.","family":"Segal","sequence":"first","affiliation":[{"name":"Hackensack University Medical Center Northeast Regional Epilepsy Group, and Hackensack Meridian School of Medicine  Hackensack New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4735-3431","authenticated-orcid":false,"given":"James W.","family":"Wheless","sequence":"additional","affiliation":[{"name":"Le Bonheur Children's Hospital University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1677-3955","authenticated-orcid":false,"given":"Muhammad","family":"Zafar","sequence":"additional","affiliation":[{"name":"Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8455-0231","authenticated-orcid":false,"given":"Evelyn K.","family":"Shih","sequence":"additional","affiliation":[{"name":"Formerly of Neurelis, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8184-1367","authenticated-orcid":false,"given":"Leock Y.","family":"Ngo","sequence":"additional","affiliation":[{"name":"Neurelis, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8788-0722","authenticated-orcid":false,"given":"Enrique","family":"Carrazana","sequence":"additional","affiliation":[{"name":"Neurelis, Inc.  San Diego California USA"},{"name":"John A. Burns School of Medicine University of Hawaii  Honolulu Hawaii USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1299-0606","authenticated-orcid":false,"given":"Adrian L.","family":"Rabinowicz","sequence":"additional","affiliation":[{"name":"Neurelis, Inc.  San Diego California USA"},{"name":"Center for Molecular Biology and Biotechnology (CMBB) in the Charles E. Schmidt Collage of Science at Florida Atlantic University  Boca Raton Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the DIAZ.001.008 Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,12]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2015.04.022"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2018.05.013"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/epd2.20243"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2018.09.035"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/NRL.0000000000000140"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/08830738020170010501"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.643916"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2009.08.006"},{"key":"e_1_2_14_10_1","volume-title":"Diastat\u00ae C\u2010IV (diazepam rectal gel)","author":"Bausch Health US, LLC","year":"2023"},{"key":"e_1_2_14_11_1","volume-title":"VALTOCO\u00ae (diazepam nasal spray). Full Prescribing Information","author":"Neurelis, Inc","year":"2025"},{"key":"e_1_2_14_12_1","volume-title":"Nayzilam\u00ae (midazolam nasal spray). Full Prescribing Information","author":"UCB, Inc","year":"2023"},{"key":"e_1_2_14_13_1","volume-title":"Buccolam summary of product characteristics (midazolam hydrochloride oromucosal solution). Summary of Product Characteristics","author":"Laboratorios Lesvi SL","year":"2023"},{"key":"e_1_2_14_14_1","unstructured":"Electronic Medicines Compendium.Diazepam Desitin 5 mg rectal solution.https:\/\/www.medicines.org.uk\/emc\/product\/2997\/smpc. Accessed September 8 2021."},{"key":"e_1_2_14_15_1","volume-title":"Nasolam (midazolam nasal spray). 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