{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T06:16:15Z","timestamp":1788243375247,"version":"build-2803163510"},"reference-count":29,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T00:00:00Z","timestamp":1589241600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"SK Life Science, Inc."}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>During the development of cenobamate, an antiseizure medication (ASM) for focal seizures, three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) occurred. To mitigate the rate of DRESS, a start\u2010low, go\u2010slow approach was studied in an ongoing, open\u2010label, multicenter study. Also examined were long\u2010term safety of cenobamate and a method for managing the pharmacokinetic interaction between cenobamate, a 2C19 inhibitor, and concomitant phenytoin or phenobarbital.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients 18\u201070\u00a0years old with uncontrolled focal seizures taking stable doses of one to three ASMs were enrolled. Cenobamate 12.5\u00a0mg\/d was initiated and increased at 2\u2010week intervals to 25, 50, 100, 150, and 200\u00a0mg\/d. Additional biweekly 50\u00a0mg\/d increases to 400\u00a0mg\/d were allowed. During titration, patients taking phenytoin or phenobarbital could not have their cenobamate titration rate or other concomitant ASMs adjusted; phenytoin\/phenobarbital doses could be decreased by 25%\u201033%.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At data cutoff (median treatment duration = 9\u00a0months), 1347 patients were enrolled, of whom 269 (20.0%) discontinued, most commonly due to adverse events (n\u00a0=\u00a0137)\u00a0and consent withdrawn for reason other than adverse event\u00a0(n\u00a0=\u00a074); 1339 patients received \u22651 treatment dose (median modal dose = 200\u00a0mg). The most common treatment\u2010emergent adverse events (TEAEs) were somnolence (28.1%), dizziness (23.6%), and fatigue (16.6%). Serious TEAEs occurred in 108 patients (8.1%), most commonly seizure (n\u00a0=\u00a014), epilepsy (n\u00a0=\u00a05), and pneumonia, fall, and dizziness (n\u00a0=\u00a04 each). No cases of DRESS were identified. In the phenytoin\/phenobarbital groups, 43.4% (36\/114) and 29.7% (11\/51) of patients, respectively, had their doses decreased. At the end of titration, mean plasma phenytoin\/phenobarbital levels were generally comparable to baseline.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>No cases of DRESS were identified in 1339 patients exposed to cenobamate using a start\u2010low (12.5\u00a0mg\/d), go\u2010slow titration approach. Cenobamate was generally well tolerated in the long term, with no new safety issues found. Phenytoin\/phenobarbital dose reductions (25%\u201033%), when needed during cenobamate titration, maintained stable plasma levels.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16525","type":"journal-article","created":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T18:20:43Z","timestamp":1589307643000},"page":"1099-1108","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":210,"title":["Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open\u2010label safety study"],"prefix":"10.1111","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0708-6006","authenticated-orcid":false,"given":"Michael R.","family":"Sperling","sequence":"first","affiliation":[{"name":"Thomas Jefferson University Philadelphia PA USA"}],"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 MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami","family":"Aboumatar","sequence":"additional","affiliation":[{"name":"Austin Epilepsy Care Center Austin TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Gelfand","sequence":"additional","affiliation":[{"name":"Hospital of the University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1681-6744","authenticated-orcid":false,"given":"Jonathan J.","family":"Halford","sequence":"additional","affiliation":[{"name":"Medical University of South Carolina Charlestown SC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory L.","family":"Krauss","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William E.","family":"Rosenfeld","sequence":"additional","affiliation":[{"name":"Comprehensive Epilepsy Care Center for Children and Adults St Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Vossler","sequence":"additional","affiliation":[{"name":"University of Washington School of Medicine Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3146-986X","authenticated-orcid":false,"given":"Robert","family":"Wechsler","sequence":"additional","affiliation":[{"name":"Consultants in Epilepsy &amp; Neurology and Idaho Comprehensive Epilepsy Center Boise ID USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leona","family":"Borchert","sequence":"additional","affiliation":[{"name":"SK Life Science, Inc. Paramus NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Kamin","sequence":"additional","affiliation":[{"name":"SK Life Science, Inc. Paramus NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,5,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200002033420503"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2001.04501.x"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13853"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12294"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2012.10.001"},{"key":"e_1_2_9_7_1","unstructured":"US Food and Drug Administration.FDA approves new treatment for adults with partial\u2010onset seizures [press release].2019. 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