{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T16:18:27Z","timestamp":1773937107724,"version":"3.50.1"},"reference-count":65,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["POCI\u201001\u20100145\u2010FEDER\u2010030478."],"award-info":[{"award-number":["POCI\u201001\u20100145\u2010FEDER\u2010030478."]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Levetiracetam is a widely used antiseizure drug in patients with refractory epilepsy due to its specific mechanism of action. This study aimed to develop and validate a population pharmacokinetic model (PopPK) to optimize levetiracetam dosing in patients with refractory epilepsy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A total of 256 plasma concentrations of levetiracetam, obtained from 135 patients, were employed for PopPK model development, applying a nonlinear mixed\u2010effects modeling methodology. Evaluation of the final model was performed by visually inspecting the goodness\u2010of\u2010fit plots generated, bootstrap resampling, and visual predictive check (VPC). In addition, 60 plasma concentrations, obtained from other 37 patients, were used for external validation of the developed model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A one\u2010compartment model with first\u2010order elimination best described the pharmacokinetic profiles of levetiracetam. Between\u2010patient variability (BPV) was included on apparent clearance (CL\/F), and the residual error (RE) was modeled as proportional. The estimates for CL\/F, apparent volume of distribution (Vd\/F), and absorption rate constant (ka) of the final model were 3.73\u2009L\/h, 35.10\u2009L, and 1.35\u2009h\n                      <jats:sup>\u22121<\/jats:sup>\n                      , respectively. BPV associated with CL\/F was 18.30%, and the proportional RE was 21.21%. The co\u2010administration of other antiseizure drugs that are metabolic inducers, the glomerular filtration rate, and the body weight were identified as significant covariates for CL\/F, whereas body surface area was the only covariate with significant impact on the Vd\/F. The bootstrap, VPC, and external evaluation collectively validated the stability and predictive performance of the final model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>A reliable PopPK model was successfully developed and validated, offering a valuable tool for tailoring levetiracetam dosing regimens and enhancing drug effectiveness and safety in adult patients with refractory epilepsy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.18312","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T09:49:11Z","timestamp":1739267351000},"page":"1505-1518","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Population pharmacokinetics of levetiracetam in patients diagnosed with refractory epilepsy: A real\u2010world study"],"prefix":"10.1111","volume":"66","author":[{"given":"Rui","family":"Silva","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy University of Coimbra  Coimbra Portugal"},{"name":"CIBIT\/ICNAS\u2014Coimbra Institute for Biomedical Imaging and Translational Research University of Coimbra  Coimbra Portugal"}]},{"given":"Helena","family":"Colom","sequence":"additional","affiliation":[{"name":"Farmacoter\u00e0pia, Farmacogen\u00e8tica i Tecnologia Farmac\u00e8utica Institut d'Investigaci\u00f3 Biom\u00e8dica de Bellvitge, IDIBELL  Hospitalet de Llobregat Spain"},{"name":"Pharmacy and Pharmaceutical Technology and Physical Chemistry Department Faculty of Pharmacy and Food Sciences, Universitat de Barcelona  Barcelona Spain"}]},{"given":"Anabela","family":"Almeida","sequence":"additional","affiliation":[{"name":"CIBIT\/ICNAS\u2014Coimbra Institute for Biomedical Imaging and Translational Research University of Coimbra  Coimbra Portugal"},{"name":"CIVG\u2014Vasco da Gama Research Center \/ EUVG\u2014Vasco da Gama University School  Coimbra Portugal"}]},{"given":"Joana","family":"Bicker","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy University of Coimbra  Coimbra Portugal"},{"name":"CIBIT\/ICNAS\u2014Coimbra Institute for Biomedical Imaging and Translational Research University of Coimbra  Coimbra Portugal"}]},{"given":"Andreia","family":"Carona","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy University of Coimbra  Coimbra Portugal"},{"name":"CIBIT\/ICNAS\u2014Coimbra Institute for Biomedical Imaging and Translational Research University of Coimbra  Coimbra Portugal"}]},{"given":"Ana","family":"Silva","sequence":"additional","affiliation":[{"name":"Refractory Epilepsy Reference Centre, Centro Hospitalar e Universit\u00e1rio de Coimbra, EPE  Coimbra 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