{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:09:39Z","timestamp":1791295779155,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,12,12]],"date-time":"2023-12-12T00:00:00Z","timestamp":1702339200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100001454","name":"American Epilepsy Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001454","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004896","name":"Eisai Incorporated","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004896","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Poor medication adherence remains a concern for individuals managing their epilepsy with antiseizure medicines (ASMs); however, ethical concerns around withholding medication make it impossible to study the causal relationship between missed doses and seizures in patients. Previous preclinical studies from our group suggest that mechanistically distinct ASMs have varying degrees of forgiveness when a dose is missed. However, with only a few ASMs studied in the context of nonadherence, we sought to expand on previous work to understand the relationship between levetiracetam (LEV) nonadherence and breakthrough seizures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Chronic oral dosing was initiated in rats with established epilepsy via our automated medication\u2010in\u2010food delivery system coupled to 24\/7 video\u2010electroencephalographic recording. Baseline seizure burden was established for 4\u2009weeks before enrolling subjects into a 4\u2010week treatment period with LEV in a 100% fully adherent (75\u2009mg\/kg four times daily) or 50% variably adherent paradigm. The temporal relationship between missed doses and breakthrough seizures was correlated with LEV plasma and brain concentrations in separate cohorts of animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Full adherence to LEV significantly improved seizure control by 50% in half of the animals. Poor adherence worsened seizure frequency by 85%, with most rats having more severe seizures that formed in clusters following missed doses. LEV concentrations remained below therapeutic levels (&lt;10\u2009\u03bcg\/mL) in nonadherent animals, with brain and plasma levels directly correlating with the degree of adherence in a 24\u2010h period. Missed doses of LEV immediately increased the risk of breakthrough seizures; however, this risk was significantly reduced with improved adherence in a 24\u2010h period.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>These findings enhance our understanding of ASM nonadherence in preclinical models, highlighting that the timing of missed doses and their impact on seizures may vary between different ASMs. Notably, LEV demonstrates a robust pharmacokinetic reliance on missed doses leading to breakthrough seizures.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17835","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T07:54:41Z","timestamp":1701330881000},"page":"497-510","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Temporal relationship between levetiracetam nonadherence and breakthrough seizures in a preclinical model of temporal lobe epilepsy"],"prefix":"10.1111","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4788-0175","authenticated-orcid":false,"given":"Michelle","family":"Guignet","sequence":"first","affiliation":[{"name":"Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Vuong","sequence":"additional","affiliation":[{"name":"Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Martinez","sequence":"additional","affiliation":[{"name":"Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ticha","family":"Ballapapinan","sequence":"additional","affiliation":[{"name":"Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Steve","family":"White","sequence":"additional","affiliation":[{"name":"Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12,12]]},"reference":[{"issue":"3","key":"e_1_2_11_2_1","first-page":"507","article-title":"Self\u2010management and its predictors in adult patients with epilepsy: a cross\u2010sectional study","volume":"33","author":"Babaei K","year":"2023","journal-title":"Ethiop J Health 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