{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T01:05:23Z","timestamp":1747184723543,"version":"3.40.5"},"reference-count":29,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T00:00:00Z","timestamp":1668038400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Lamotrigine is a commonly prescribed antiepileptic drug. U.S. Food and Drug Administration (FDA)\u2013funded clinical studies have demonstrated bioequivalence (BE) for generic lamotrigine immediate\u2010release (IR) products in epilepsy patients with generic substitution. To address the potential concerns about the risk of generic\u2010brand substitution of lamotrigine extended\u2010release (ER) products, considering the complexity of controlled release systems and pharmacokinetic variations associated with possible within\u2010subject variability (WSV), this prospective study assessed (1) BE of generic and brand lamotrigine ER products in a fully replicated BE study design in healthy subjects and (2) whether such fully replicated study design and WSV data can better support the approval of generic lamotrigine ER products.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This open\u2010label, single\u2010dose, two\u2010treatment, four\u2010period, two\u2010sequence, fully replicated crossover BE study compared generic lamotrigine ER tablet to brand Lamictal XR (200\u2009mg) in 30 healthy subjects under fed conditions. Pharmacokinetics (PK) profiles were generated based on intensive blood sampling up to 144\u2009h.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The two products showed comparable peak plasma concentration (C<jats:sub>max<\/jats:sub>), area under the concentration\u2010time curve (AUC) from time zero to the last measurable time point (AUC<jats:sub>0\u2010t<\/jats:sub>) and AUC extrapolated to infinity (AUC<jats:sub>0\u2010inf<\/jats:sub>), whereas median time to C<jats:sub>max<\/jats:sub>(T<jats:sub>max<\/jats:sub>) values differed, that is, 10\u00a0h for generic and 22\u2009h for brand products, respectively. WSVs for PK metrics were small (~8% of C<jats:sub>max<\/jats:sub>and ~6% of AUC) and similar between these two products. PK simulation predicted equivalent PK measurements of both products at steady state and after brand\u2010to\u2010generic switch, except the first day upon switching. No serious adverse events were reported.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>The generic lamotrigine ER tablet product demonstrates BE to the brand product in a fully replicated BE study design with healthy subjects, supporting the adequacy of the two\u2010way crossover study design to demonstrate BE and generic\u2010brand substitution of lamotrigine ER products.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17438","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T06:49:08Z","timestamp":1666162148000},"page":"152-161","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Generic lamotrigine extended\u2010release tablets are bioequivalent to innovator drug in fully replicated crossover bioequivalence study"],"prefix":"10.1111","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5378-2948","authenticated-orcid":false,"given":"Lanyan","family":"Fang","sequence":"first","affiliation":[{"name":"Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research U.S. Food and Drug Administration Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhichuan","family":"Li","sequence":"additional","affiliation":[{"name":"Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research U.S. Food and Drug Administration Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minori","family":"Kinjo","sequence":"additional","affiliation":[{"name":"Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research U.S. Food and Drug Administration Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Lomonaco","sequence":"additional","affiliation":[{"name":"Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research U.S. Food and Drug Administration Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research U.S. Food and Drug Administration Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenlei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research U.S. Food and Drug Administration Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research U.S. Food and Drug Administration Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,11,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.5698\/1535-7597.18.4s1.1"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2016.1254041"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.2147\/TCRM.S3343"},{"key":"e_1_2_11_5_1","unstructured":"U.S. Food and Drug Administration.Approved drug products with therapeutic equivalence evaluation.42nd Edition. 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