{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T12:06:53Z","timestamp":1785240413417,"version":"3.55.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Cenobamate (CNB) demonstrates high efficacy in drug-resistant focal epilepsy, yet optimal management requires personalized strategies. This exploratory case series describes five patients selected from a cohort of 125 individuals treated with CNB, examining the relationship between pharmacogenetic (PGx) profiles and clinical outcomes. Clinical data and therapeutic drug monitoring (TDM) were integrated with targeted Next-Generation Sequencing of key metabolic genes (UGT2B7, UGT2B4, CYP2E1, CYP2B6, CYP2A6, CYP3A4, CYP2C19) to predict metabolizer phenotypes. Three patients (Cases 1, 3, 4) achieved seizure freedom or \u226550% response at sub-target or target doses (100\u2013200\u00a0mg\/day\n                    <jats:italic>)<\/jats:italic>\n                    enabling early de-escalation of concomitant sodium channel blockers and valproate. This success was supported by a proactive digital communication protocol and a mandatory 100\u00a0mg clinical checkpoint. Case 2\u2014a non-responder at 400\u00a0mg\/day despite therapeutic plasma levels (28.22\u00a0mg\/L)\u2014exhibited a predicted \u201cUltrarapid Metabolizer\u201d (UM) phenotype characterized by UGT2B7 Haplotype 4 and CYP2E1 duplication, suggesting possible pharmacokinetic contribution to non-response. Case 5 experienced dose-limiting toxicity at 100\u00a0mg\/day; we hypothesized this toxicity could be driven by a drug-drug-gene interaction involving CNB-mediated\n                    <jats:italic>CYP2C19<\/jats:italic>\n                    inhibition that impairs clearance of N-desmethylclobazam (the active metabolite of clobazam) in a patient with impaired\n                    <jats:italic>CYP2A6<\/jats:italic>\n                    activity and intermediate\n                    <jats:italic>UGT2B7<\/jats:italic>\n                    function. As an exploratory case series, these findings require validation in adequately powered prospective studies. Associations between UM phenotype and non-response, and between PM phenotype and dose-limiting toxicity, represent preliminary observations that may reflect pharmacokinetic variability. Nevertheless, our experience is consistent with a personalized, sub-target dose titration strategy that may help minimize adverse events in complex polypharmacy settings.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1830217","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T05:40:15Z","timestamp":1780551615000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Precision management of cenobamate in drug-resistant epilepsy: integrating pharmacogenetics, therapeutic drug monitoring, and real-world clinical strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"Giuseppe","family":"d\u2019Orsi","sequence":"first","affiliation":[{"name":"Neurology Unit - Epilepsy Center, Fondazione IRCCS Casa Sollievo Della Sofferenza","place":["San Giovanni Rotond, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa","family":"Di Claudio","sequence":"additional","affiliation":[{"name":"Neurology Unit - Epilepsy Center, Fondazione IRCCS Casa Sollievo Della Sofferenza","place":["San Giovanni Rotond, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Cafaro","sequence":"additional","affiliation":[{"name":"Biochemistry, Pharmacology and Newborn Screening Unit, Central Laboratory of Analyses, IRCCS Istituto Giannina Gaslini","place":["Genova, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Barco","sequence":"additional","affiliation":[{"name":"Biochemistry, Pharmacology and Newborn Screening Unit, Central Laboratory of Analyses, IRCCS Istituto Giannina Gaslini","place":["Genova, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Robustella","sequence":"additional","affiliation":[{"name":"Neurology Unit - Epilepsy Center, Fondazione IRCCS Casa Sollievo Della Sofferenza","place":["San Giovanni Rotond, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicol\u00f2","family":"Locatelli","sequence":"additional","affiliation":[{"name":"Neurology Unit - Epilepsy Center, Fondazione IRCCS Casa Sollievo Della Sofferenza","place":["San Giovanni Rotond, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Liantonio","sequence":"additional","affiliation":[{"name":"Department of Pharmacy - Drug Sciences, University of Bari \u201cAldo Moro\u201d","place":["Bari, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Imbrici","sequence":"additional","affiliation":[{"name":"Department of Pharmacy - Drug Sciences, University of Bari \u201cAldo Moro\u201d","place":["Bari, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Ciavarella","sequence":"additional","affiliation":[{"name":"Medicina Trasfusionale e Laboratorio Analisi, Fondazione IRCCS Casa Sollievo Della Sofferenza","place":["San Giovanni Rotondo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Rinaldi","sequence":"additional","affiliation":[{"name":"Medicina Trasfusionale e Laboratorio Analisi, Fondazione IRCCS Casa Sollievo Della Sofferenza","place":["San Giovanni Rotondo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Fania","sequence":"additional","affiliation":[{"name":"Medicina Trasfusionale e Laboratorio Analisi, Fondazione IRCCS Casa Sollievo Della Sofferenza","place":["San Giovanni Rotondo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umberto","family":"Costantino","sequence":"additional","affiliation":[{"name":"Neurology Unit - Epilepsy Center, Fondazione IRCCS Casa Sollievo Della Sofferenza","place":["San Giovanni Rotond, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Carella","sequence":"additional","affiliation":[{"name":"UOC Genetica Medica, Fondazione IRCCS Casa Sollievo Della Sofferenza","place":["San Giovanni Rotondo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Cangemi","sequence":"additional","affiliation":[{"name":"Biochemistry, Pharmacology and Newborn Screening Unit, Central Laboratory of Analyses, IRCCS Istituto Giannina Gaslini","place":["Genova, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Miscio","sequence":"additional","affiliation":[{"name":"Medicina Trasfusionale e Laboratorio Analisi, Fondazione IRCCS Casa Sollievo Della Sofferenza","place":["San Giovanni Rotondo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"B2","doi-asserted-by":"publisher","first-page":"e2311","DOI":"10.1212\/WNL.0000000000009530","article-title":"Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures","volume":"94","author":"Chung","year":"2020","journal-title":"Neurology"},{"key":"B35","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1002\/cpt.2166","article-title":"PharmVar GeneFocus: CYP2B6","volume":"110","author":"Desta","year":"2021","journal-title":"Clin. Pharmacol. Ther."},{"key":"B3","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1097\/00008571-199812000-00011","article-title":"Detection and characterization of novel polymorphisms in the CYP2E1 gene","volume":"8","author":"Fairbrother","year":"1998","journal-title":"Pharmacogenetics"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1124\/dmd.105.004994","article-title":"Characterization of novel CYP2A6 polymorphic alleles (CYP2A618 and CYP2A619) that affect enzymatic activity","volume":"33","author":"Fukami","year":"2005","journal-title":"Drug Metab. Dispos."},{"key":"B5","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1248\/bpb.35.394","article-title":"Functional characterization of allelic variants of polymorphic human cytochrome P450 2A6 (CYP2A65, 7, 8, 18, 19, and 35)","volume":"35","author":"Han","year":"2012","journal-title":"Biol. Pharm. Bull."},{"key":"B6","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1124\/dmd.113.056572","article-title":"Polymorphisms and haplotypes of the UDP-glucuronosyltransferase 2B7 gene promoter","volume":"42","author":"Hu","year":"2014","journal-title":"Drug Metab. Dispos."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e40883","DOI":"10.1371\/journal.pone.0040883","article-title":"Systematic functional characterization of cytochrome P450 2E1 promoter variants in the Chinese Han population","volume":"7","author":"Huang","year":"2012","journal-title":"PLoS One"},{"key":"B8","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1097\/FPC.0b013e3283037fe4","article-title":"Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene","volume":"18","author":"Innocenti","year":"2008","journal-title":"Pharmacogenet Genomics"},{"key":"B9","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/nrd1801","article-title":"Pharmacogenetics-based therapeutic recommendations\u2014Ready for clinical practice?","volume":"4","author":"Kirchheiner","year":"2005","journal-title":"Nat. Rev. Drug Discov."},{"key":"B10","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/S1474-4422(19)30399-0","article-title":"Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial","volume":"19","author":"Krauss","year":"2020","journal-title":"Lancet Neurol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1111\/j.1528-1167.2009.02397.x","article-title":"Definition of drug resistant epilepsy: consensus proposal by the ad hoc task force of the ILAE commission on therapeutic strategies","volume":"51","author":"Kwan","year":"2010","journal-title":"Epilepsia"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1177\/0091270009338482","article-title":"Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB\/HIV-coinfected Ghanaian patients: UGT2B71c is associated with faster zidovudine clearance and glucuronidation","volume":"49","author":"Kwara","year":"2009","journal-title":"J. Clin. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1002\/cpt.3387","article-title":"PharmVar GeneFocus: CYP2A6","volume":"116","author":"Langlois","year":"2024","journal-title":"Clin. Pharmacol. Ther."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2239","DOI":"10.1111\/epi.18357","article-title":"Effectiveness and safety of adjunctive cenobamate in people with focal-onset epilepsy: interim results after 24-week observational period from the BLESS study","volume":"66","author":"Lattanzi","year":"2025","journal-title":"Epilepsia"},{"key":"B15","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.ejphar.2019.05.007","article-title":"Effects of cenobamate (YKP3089), a newly developed anti-epileptic drug, on voltage-gated sodium channels in rat hippocampal CA3 neurons","volume":"855","author":"Nakamura","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1111\/epi.17874","article-title":"Add-on treatment with cenobamate is already effective at low doses in refractory focal epilepsy: a prospective observational study","volume":"65","author":"Novitskaya","year":"2024","journal-title":"Epilepsia"},{"key":"B17","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1002\/humu.10126","article-title":"Characterization of a novel CYP2A7\/CYP2A6 hybrid allele (CYP2A612) that causes reduced CYP2A6 activity","volume":"20","author":"Oscarson","year":"2002","journal-title":"Hum. Mutat."},{"key":"B18","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/S1474-4422(03)00483-6","article-title":"Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs","volume":"2","author":"Patsalos","year":"2003","journal-title":"Lancet Neurol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1111\/epi.17549","article-title":"Adjunctive cenobamate in highly active and ultra-refractory focal epilepsy: a \u201creal-world\u201d retrospective study","volume":"64","author":"Pe\u00f1a-Ceballos","year":"2023","journal-title":"Epilepsia"},{"key":"B20","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1007\/s40263-023-01027-2","article-title":"New GABA-Targeting therapies for the treatment of seizures and epilepsy: I. Role of GABA as a modulator of seizure activity and recently approved medications acting on the GABA system","volume":"37","author":"Perucca","year":"2023","journal-title":"CNS Drugs"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2144","DOI":"10.1002\/epi4.12927","article-title":"A VAMS-based LC-MS\/MS method for precise cenobamate quantification in epilepsy patients","volume":"9","author":"Pigliasco","year":"2024","journal-title":"Epilepsia Open"},{"key":"B22","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/nature15817","article-title":"Pharmacogenomics in the clinic","volume":"526","author":"Relling","year":"2015","journal-title":"Nature"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2163","DOI":"10.2174\/1570159X19666210517112408","article-title":"Cenobamate: a novel antiseizure medication with dual mechanism of action","volume":"19","author":"Sharma","year":"2021","journal-title":"Curr. Neuropharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1016\/B978-0-444-52899-5.00024-4","article-title":"Pharmacogenetics of antiepileptic drugs","volume":"108","author":"Sisodiya","year":"2012","journal-title":"Handb. Clin. Neurol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1111\/epi.16525","article-title":"Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study","volume":"61","author":"Sperling","year":"2020","journal-title":"Epilepsia"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2757","DOI":"10.3390\/jcm13102757","article-title":"Cenobamate plasma levels in patients with epilepsy: correlation with efficacy and tolerability?","volume":"13","author":"Steinhoff","year":"2024","journal-title":"J. Clin. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3390\/jpm7040018","article-title":"Variation in CYP2A6 activity and personalized medicine","volume":"7","author":"Tanner","year":"2017","journal-title":"J. Pers. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1097\/FPC.0000000000000317","article-title":"Novel CYP2A6 diplotypes identified through next-generation sequencing are associated with in-vitro and in-vivo nicotine metabolism","volume":"28","author":"Tanner","year":"2018","journal-title":"Pharmacogenet Genomics"},{"key":"B29","doi-asserted-by":"publisher","first-page":"S34","DOI":"10.1038\/ng1437","article-title":"Will tomorrow's medicines work for everyone?","volume":"36","author":"Tate","year":"2004","journal-title":"Nat. Genet."},{"key":"B30","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/tpj.2015.75","article-title":"Gene copy number variation analysis reveals dosage-insensitive expression of CYP2E1","volume":"16","author":"Tremmel","year":"2016","journal-title":"Pharmacogenomics J."},{"key":"B31","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1007\/s40262-019-00832-5","article-title":"Clinical pharmacokinetics and pharmacodynamics of cenobamate","volume":"59","author":"Vernillet","year":"2020","journal-title":"Clin. Pharmacokinet."},{"key":"B32","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1080\/14737175.2023.2171291","article-title":"Use of cenobamate for the treatment of focal epilepsy: an Italian expert opinion paper","volume":"22","author":"Villani","year":"2022","journal-title":"Expert Rev. Neurother."},{"key":"B33","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1002\/epi4.12757","article-title":"Real-world safety and effectiveness of cenobamate in patients with focal onset seizures: outcomes from an expanded access program","volume":"8","author":"Villanueva","year":"2023","journal-title":"Epilepsia Open"},{"key":"B34","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.jsbmb.2010.12.014","article-title":"Associations between polymorphisms in glucuronidation and sulfation enzymes and sex steroid concentrations in premenopausal women in the United States","volume":"124","author":"Yong","year":"2011","journal-title":"J. Steroid Biochem. Mol. Biol."}],"updated-by":[{"DOI":"10.3389\/fphar.2026.1939779","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000}}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1830217\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T11:47:01Z","timestamp":1785239221000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1830217\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,4]]},"references-count":34,"alternative-id":["10.3389\/fphar.2026.1830217"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1830217","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,4]]},"article-number":"1830217"}}