{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T14:46:56Z","timestamp":1786546016609,"version":"build-2736575974"},"reference-count":19,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,4,27]],"date-time":"2020-04-27T00:00:00Z","timestamp":1587945600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Neurelis, Inc."}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To assess pharmacokinetics and safety of diazepam nasal spray (NRL\u20101; VALTOCO\u00ae) in pediatric and adult patients with epilepsy in seizure and nonseizure states.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A single dose of diazepam nasal spray (5, 10, 15, or 20\u00a0mg based on weight) was administered during each of two conditions (ictal\/peri\u2010ictal and interictal condition) to patients 6\u201065\u00a0years old with partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness; a second dose was permitted if needed for persistent seizures. Dosing could be interictal or ictal\/peri\u2010ictal first, with a washout of \u226514\u00a0days. Blood samples for pharmacokinetic analysis were taken at prespecified time points. Treatment\u2010emergent adverse events (TEAEs), sedation, nasal irritation, nasal mucosal pain, and olfactory changes were assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of 57 patients in the study (mean age = 28.1\u00a0years [range = 6\u201059], 54.4% female, 80.7% white), 49 were included in the primary pharmacokinetic analyses. Diazepam pharmacokinetic profiles were similar under both conditions, with approximately 2\u2010hour median time to mean (SD) maximum plasma concentrations of 164 (88) and 189 (110) ng\/mL for ictal\/peri\u2010ictal and interictal conditions, respectively; drug exposure during the first 6\u00a0hours postdosing was 532 (313) and 615 (368) h\u2022ng\/mL, respectively. Seventeen patients (29.8%) reported TEAEs, of whom eight (14%) had treatment\u2010related TEAEs, with those reported in \u22652 patients being dysgeusia (n\u00a0=\u00a03, 5.3%) and nasal discomfort (n\u00a0=\u00a02, 3.5%). One patient had serious TEAEs (recurrent seizures, metabolic encephalopathy), which were deemed unrelated to study treatment. No changes in respiratory rate were observed, nor were there clinically relevant changes in sedation, olfaction, nasal irritation, or acute nasal mucosal pain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>The epileptic conditions (ictal\/peri\u2010ictal, interictal) had minimal impact on diazepam nasal spray pharmacokinetics in patients with epilepsy. Therefore, diazepam nasal spray can be administered ictally and interictally. Diazepam nasal spray safety was consistent with the profile of diazepam.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16506","type":"journal-article","created":{"date-parts":[[2020,4,27]],"date-time":"2020-04-27T08:12:54Z","timestamp":1587975174000},"page":"935-943","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Pharmacokinetics and safety of VALTOCO (NRL\u20101; diazepam nasal spray) in patients with epilepsy during seizure (ictal\/peri\u2010ictal) and nonseizure (interictal) conditions: A phase 1, open\u2010label study"],"prefix":"10.1111","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2272-5005","authenticated-orcid":false,"given":"Robert Edward","family":"Hogan","sequence":"first","affiliation":[{"name":"Washington University in St Louis St Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Tarquinio","sequence":"additional","affiliation":[{"name":"Center for Rare Neurological Diseases Atlanta Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0708-6006","authenticated-orcid":false,"given":"Michael R.","family":"Sperling","sequence":"additional","affiliation":[{"name":"Thomas Jefferson University Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7244-3722","authenticated-orcid":false,"given":"Pavel","family":"Klein","sequence":"additional","affiliation":[{"name":"Mid\u2010Atlantic Epilepsy and Sleep Center Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Miller","sequence":"additional","affiliation":[{"name":"Nicklaus Children\u2019s Hospital Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric B.","family":"Segal","sequence":"additional","affiliation":[{"name":"Hackensack University Medical Center Hackensack Meridian School of Medicine and Northeast Regional Epilepsy Group Hackensack New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian L.","family":"Rabinowicz","sequence":"additional","affiliation":[{"name":"Neurelis San Diego California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Carrazana","sequence":"additional","affiliation":[{"name":"Consultant for Neurelis San Diego California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,27]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2018.05.013"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2010.10.001"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2016.07.001"},{"key":"e_1_2_9_5_1","unstructured":"Acorda Therapeutics.PLUMIAZ\u2122 (diazepam) nasal spray[press release]. 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Available at:http:\/\/ir.acorda.com\/investors\/investor\u2010news\/investor\u2010news\u2010details\/2016\/Acorda\u2010to\u2010Discontinue\u2010Development\u2010of\u2010PLUMIAZ\u2010for\u2010Treatment\u2010of\u2010Epilepsy\u2010Seizure\u2010Clusters\/default.aspx"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.15159"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13346-012-0069-z"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16449"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2013.02.018"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.767"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2011.10111704"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182872eb4"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.14069"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1213\/00000539-198301000-00001"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1998.tb01415.x"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2014.04.007"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.2165\/11590250-000000000-00000"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2012.07.018"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/head.12905"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1384"}],"updated-by":[{"DOI":"10.1111\/epi.16734","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,11,2]],"date-time":"2020-11-02T00:00:00Z","timestamp":1604275200000}}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fepi.16506","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.16506","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/epi.16506","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.16506","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T02:40:48Z","timestamp":1693968048000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.16506"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,27]]},"references-count":19,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,5]]}},"alternative-id":["10.1111\/epi.16506"],"URL":"https:\/\/doi.org\/10.1111\/epi.16506","archive":["Portico"],"relation":{"correction":[{"id-type":"doi","id":"10.1111\/epi.16734","asserted-by":"object"}]},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,27]]},"assertion":[{"value":"2020-02-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-25","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-04-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}