{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T23:08:04Z","timestamp":1776294484419,"version":"3.50.1"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T00:00:00Z","timestamp":1696377600000},"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":["Fundamemntal Clinical Pharma"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Valproate inhibits clearance of lamotrigine and greatly increases its concentrations. We assessed whether this effect was moderated by a polymorphism (<jats:italic>ABCG2 c.421C&gt;A<\/jats:italic>) of the breast cancer resistance protein.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In two consecutive independent studies in adults with epilepsy on lamotrigine monotherapy or cotreated with valproate: (i) Exposure to valproate was considered treatment, (ii) dose\u2010adjusted lamotrigine troughs at steady state were the outcome, and (iii) <jats:italic>ABCG2 c.421C&gt;A<\/jats:italic> genotype (wild\u2010type [wt] homozygosity or variant carriage) was the tested moderator. We used entropy balancing (primary analysis) and exact\/optimal full matching (secondary analysis) to control for confounding, including polymorphisms (and linked polymorphisms) suggested to affect exposure to lamotrigine (<jats:italic>UGT1A4*3 c.142T&gt;G<\/jats:italic>, rs2011425; <jats:italic>UGT2B7\u2013161C&gt;T<\/jats:italic>, rs7668258; <jats:italic>ABCB1 1236C&gt;T<\/jats:italic>, rs1128503) to generate frequentist and Bayesian estimates of valproate effects (geometric means ratios [GMR]).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The two studies yielded consistent results (replicated); hence, we analyzed combined data (total <jats:italic>N<\/jats:italic>\u00a0=\u2009471, 140 treated, 331 controls, 378 <jats:italic>ABCG2 c.421C&gt;A<\/jats:italic> wt subjects, 93 variant carriers). Primary analysis: in variant carriers, valproate effect (GMR) on lamotrigine (treated, <jats:italic>n<\/jats:italic>\u00a0=\u200921 vs. controls, <jats:italic>n<\/jats:italic>\u00a0=\u200972) was around 60% higher than in wt subjects (treated, <jats:italic>n<\/jats:italic>\u00a0=\u2009119 vs. controls, <jats:italic>n<\/jats:italic>\u00a0=\u2009259)\u2014ratio of GMRs 1.61 (95%CI 1.23\u20132.11) (frequentist) and 1.63 (95%CrI 1.26\u20132.10) (Bayes). Similar differences in valproate effects between variant carriers and wt subjects were found in the secondary analysis (valproate troughs up to 364\u00a0\u03bcmol\/L vs. no valproate; or valproate \u2265364\u00a0\u03bcmol\/L vs. no valproate). Susceptibility of the estimates to unmeasured confounding was low.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Data suggest that polymorphism rs2231142 moderates the effect of valproate on exposure to lamotrigine.<\/jats:p><\/jats:sec>","DOI":"10.1111\/fcp.12958","type":"journal-article","created":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T19:07:31Z","timestamp":1696532851000},"page":"351-368","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Breast cancer resistance protein polymorphism <i>ABCG2 c.421C&gt;A<\/i> (rs2231142) moderates the effect of valproate on lamotrigine trough concentrations in adults with epilepsy"],"prefix":"10.1111","volume":"38","author":[{"given":"Ivana","family":"\u0160u\u0161ak Spori\u0161","sequence":"first","affiliation":[{"name":"Department of Neurology University Hospital Dubrava  Zagreb Croatia"},{"name":"Faculty of Dental Medicine and Health Josip Juraj Strossmayer University of Osijek  Osijek Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nada","family":"Bo\u017eina","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Zagreb University School of Medicine  Zagreb Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iva","family":"Klarica Domjanovi\u0107","sequence":"additional","affiliation":[{"name":"Croatian Agency for Medicinal Products and Medical Devices  Zagreb Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davor","family":"Spori\u0161","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital Dubrava  Zagreb Croatia"},{"name":"Faculty of Dental Medicine and Health Josip Juraj Strossmayer University of Osijek  Osijek Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvio","family":"Ba\u0161i\u0107","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital Dubrava  Zagreb Croatia"},{"name":"Faculty of Dental Medicine and Health Josip Juraj Strossmayer University of Osijek  Osijek Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivana","family":"Ba\u0161i\u0107","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital Dubrava  Zagreb Croatia"},{"name":"Faculty of Dental Medicine and Health Josip Juraj Strossmayer University of Osijek  Osijek Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mila","family":"Lovri\u0107","sequence":"additional","affiliation":[{"name":"Analytical Toxicology and Pharmacology Division, Department of Laboratory Diagnostics University Hospital Centre Zagreb  Zagreb Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lana","family":"Ganoci","sequence":"additional","affiliation":[{"name":"Division of Pharmacogenomics and Therapy Individualization, Department of Laboratory Diagnostics University Hospital Centre Zagreb  Zagreb Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0968-1194","authenticated-orcid":false,"given":"Vladimir","family":"Trkulja","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Zagreb University School of Medicine  Zagreb Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,10,4]]},"reference":[{"key":"e_1_2_12_2_1","unstructured":"Medicines.org.uk Lamictal. 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