{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:58:13Z","timestamp":1792108693551,"version":"4.4.0"},"reference-count":23,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Cenobamate (CNB) is a new antiseizure medication (ASM) for add\u2010on therapy in adults with refractory epilepsy. The purpose of this study was to investigate the pharmacokinetic variability of CNB and extent of interactions with other ASMs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this observational therapeutic drug monitoring (TDM) study we included all patients with serum concentrations of CNB and concomitantly used ASMs (2022\u20132025) from the Section for Clinical Pharmacology, National Center for Epilepsy, Oslo University Hospital.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Data from 258 patients included 672 serum CNB concentration measurements (1\u20137 per patient; 56% women; median age\u2009=\u200936\u2009years, range\u2009=\u200911\u201377). Mean daily dose and serum concentration at the most recent measurement were 164\u2009mg\/day (range\u2009=\u200912.5\u2013400, SD\u2009=\u200988.6) and 53.7\u2009\u03bcmol\u2009L\n                      <jats:sup>\u22121<\/jats:sup>\n                      (range 5\u2013186, SD\u2009=\u200934.8). Intraindividual variation in CNB concentration\/dose (C\/D) ratios ranged from 6% to 33% (coefficient of variation\u2009=\u200918%); interpatient variability was 34\u2010fold. Comedication was a contributing but variable factor. Mean CNB C\/D ratios were affected by strong enzyme inducers (\u22129%) and inhibitors (+14%) as compared to neutral ASMs (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05). Twenty\u2010four concomitant ASMs were used (1\u20136 per patient, mean\u2009=\u20091.91, SD\u2009=\u2009.94); clobazam, lamotrigine, and valproate were the most common. After initiating CNB, significant but variable increases in mean C\/D ratios of desmethylclobazam (+233%, and +344% for the Cd\u2010clb\/Cclb\u20ac ratio,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200957) and phenobarbital (+36%,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200915) were observed, as were decreases for lamotrigine (\u221228%,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200957) and carbamazepine (\u221226%,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20097) (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05). For most other ASMs, there were unpredictable changes in individual C\/D ratios.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>We demonstrate complex and unpredictable two\u2010way interactions in polytherapy with CNB and pronounced pharmacokinetic variability among patients with refractory epilepsy, elucidating the usefulness of TDM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70184","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T15:41:11Z","timestamp":1774366871000},"page":"2820-2835","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacokinetic variability and complex two\u2010way interactions with cenobamate in patients with refractory epilepsy"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0877-8912","authenticated-orcid":false,"given":"Cecilie","family":"Johannessen Landmark","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Faculty of Health Sciences Oslo Metropolitan University  Oslo Norway"},{"name":"Section for Clinical Pharmacology, National Center for Epilepsy, Department of Pharmacology Oslo University Hospital  Oslo Norway"},{"name":"National Center for Epilepsy Oslo University Hospital, Full member of the ERN EpiCare  Sandvika Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba","family":"Belkilani","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Health Sciences Oslo Metropolitan University  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilyana","family":"Awad","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Health Sciences Oslo Metropolitan University  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margrete Larsen","family":"Burns","sequence":"additional","affiliation":[{"name":"Section for Clinical Pharmacology, National Center for Epilepsy, Department of Pharmacology Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Gott\u00e5s","sequence":"additional","affiliation":[{"name":"Section for Clinical Pharmacology, National Center for Epilepsy, Department of Pharmacology Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torleiv","family":"Svendsen","sequence":"additional","affiliation":[{"name":"National Center for Epilepsy Oslo University Hospital, Full member of the ERN EpiCare  Sandvika Norway"},{"name":"Lillehammer Trust Hospital  Lillehammer Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"S\u00e6tre","sequence":"additional","affiliation":[{"name":"National Center for Epilepsy Oslo University Hospital, Full member of the ERN EpiCare  Sandvika Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"Cenobamate Summary of product information (SPC). 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[cited Jun 8]. Available from:https:\/\/recipe.de\/products\/antiepileptic\u2010drugs\u2010serum"},{"key":"e_1_2_11_15_1","unstructured":"EMA guidelines for method validation. [cited 2025 Oct 4]. Available from:https:\/\/www.ema.europa.eu\/en\/ich\u2010m10\u2010bioanalytical\u2010method\u2010validation\u2010scientific\u2010guideline"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000272"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e31827ada88"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2025.1571376"},{"key":"e_1_2_11_19_1","doi-asserted-by":"crossref","unstructured":"VijanA XueH ChandlerP MadhavanS.Phase 1 open\u2010label fixed\u2010sequece bidirectional pharmacokinetic drug\u2010drug interaction study between cannabidiol and cenobamate in healthy adult participants. Abstract no. 1545 American Epilepsy Society Annual meeting 2025 06.12.2025. Available from:https:\/\/aesnet.org\/abstractslisting\/phase\u20101\u2010open\u2010label\u2010fixed\u2010sequence\u2010bidirectional\u2010pharmacokinetic\u2010drug\u2010drug\u2010interaction\u2010study\u2010between\u2010cannabidiol\u2010and\u2010cenobamate\u2010in\u2010healthy\u2010adult\u2010participants","DOI":"10.1212\/WNL.0000000000215597"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.18091"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2021.108270"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40120-022-00400-5"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.18304"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/ane.13206"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi.70184","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/epi.70184","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi.70184","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T12:24:24Z","timestamp":1782131064000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/epi.70184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,24]]},"references-count":23,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1002\/epi.70184"],"URL":"https:\/\/doi.org\/10.1002\/epi.70184","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,24]]},"assertion":[{"value":"2025-12-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}