{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T16:41:45Z","timestamp":1788885705103,"version":"build-2803163510"},"reference-count":30,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T00:00:00Z","timestamp":1578528000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Neurelis, Inc."}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>NRL\u20101 is a novel intranasal formulation of diazepam that is being evaluated as rescue medication in patients with epilepsy who experience bouts of increased seizure activity despite stable regimens of antiepileptic drugs. This phase 1, open\u2010label, randomized, crossover study in healthy adult volunteers consisted of 3 single\u2010dose periods (5, 10, and 20\u00a0mg) followed by a 2\u2010dose period (2\u00a0\u00d7\u00a010\u00a0mg) with a minimum 28\u2010day washout between treatments. Blood samples were taken at prespecified time points after intranasal dosing, and bioanalytic analysis of diazepam and nordiazepam was conducted using a validated liquid chromatography\u2013tandem mass spectrometry method. Plasma pharmacokinetic parameters were summarized using descriptive statistics, and dose proportionality (peak concentration [C<jats:sub>max<\/jats:sub>] and area under the plasma concentration\u2013time curve [AUC<jats:sub>0\u2010\u221e<\/jats:sub>]) was evaluated based on a power model within a 90%CI of 0.84 to 1.16. Comparisons were also conducted between single 10\u2010mg dose and multidose (2\u00a0\u00d7\u00a010\u00a0mg) treatments. NRL\u20101 administration resulted in rapid diazepam absorption (median time to peak concentration 1.4\u20101.5 hours). Plasma concentration\u2010time profiles showed similar patterns of exposure that appeared to be dose dependent, with C<jats:sub>max<\/jats:sub> of 85.6, 133.6, and 235.3\u00a0ng\/mL for the 5\u2010, 10\u2010, and 20\u2010mg doses, respectively, although the lower 90%CI for C<jats:sub>max<\/jats:sub> and AUC<jats:sub>0\u2010\u221e<\/jats:sub> exceeded dose proportionality criteria. The coefficient of variation ranged from 59% to 67% for C<jats:sub>max<\/jats:sub> and 48% to 56% for AUC parameters. Dose\u2010normalized AUC<jats:sub>0\u2013\u221e<\/jats:sub> values were comparable between the 2\u00a0\u00d7\u00a010\u2010mg and single 10\u2010mg doses. Treatment\u2010emergent adverse events were consistent with those expected for diazepam, with transient somnolence the most frequent adverse event (94.4%). These results support NRL\u20101 as a potential therapy for managing seizure emergencies.<\/jats:p>","DOI":"10.1002\/cpdd.767","type":"journal-article","created":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T12:10:31Z","timestamp":1578571831000},"page":"719-727","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Evaluation of Pharmacokinetics and Dose Proportionality of Diazepam After Intranasal Administration of NRL\u20101 to Healthy Volunteers"],"prefix":"10.1002","volume":"9","author":[{"given":"Sarina","family":"Tanimoto","sequence":"first","affiliation":[{"name":"Pacific Link Consulting  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luana","family":"Pesco Koplowitz","sequence":"additional","affiliation":[{"name":"DUCK FLATS Pharma  Elbridge New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard E.","family":"Lowenthal","sequence":"additional","affiliation":[{"name":"Pacific Link Consulting  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry","family":"Koplowitz","sequence":"additional","affiliation":[{"name":"DUCK FLATS Pharma  Elbridge New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian L.","family":"Rabinowicz","sequence":"additional","affiliation":[{"name":"Neurelis, Inc  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Carrazana","sequence":"additional","affiliation":[{"name":"Neurelis, Inc  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,1,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30454-X"},{"key":"e_1_2_10_3_1","unstructured":"Centers for Disease Control and Prevention. Epilepsy Data and Statistics.https:\/\/www.cdc.gov\/epilepsy\/data\/index.html. Accessed April 22 2019."},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2014.05.031"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2018.05.013"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2016.07.001"},{"key":"e_1_2_10_7_1","unstructured":"Acorda Therapeutics. PLUMIAZ\u2122 (diazepam) Nasal Spray [press release].http:\/\/www.acorda.com\/products\/research-development\/plumiaz. Accessed July 1 2019."},{"issue":"9","key":"e_1_2_10_8_1","first-page":"768","article-title":"Best BETs from the Manchester Royal Infirmary. 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