{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T21:44:27Z","timestamp":1764020667353,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,6,10]],"date-time":"2023-06-10T00:00:00Z","timestamp":1686355200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FEDER funds","award":["POCI-01-0145-FEDER-030478"],"award-info":[{"award-number":["POCI-01-0145-FEDER-030478"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia (FCT), Portuguese Agency for Scientific Research","award":["POCI-01-0145-FEDER-030478"],"award-info":[{"award-number":["POCI-01-0145-FEDER-030478"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Perampanel is a promising antiepileptic drug (AED) for refractory epilepsy treatment due to its innovative mechanism of action. This study aimed to develop a population pharmacokinetic (PopPK) model to be further used in initial dose optimization of perampanel in patients diagnosed with refractory epilepsy. A total of seventy-two plasma concentrations of perampanel obtained from forty-four patients were analyzed through a population pharmacokinetic approach by means of nonlinear mixed effects modeling (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic profiles of perampanel. Interpatient variability (IPV) was entered on clearance (CL), while the residual error (RE) was modeled as proportional. The presence of enzyme-inducing AEDs (EIAEDs) and body mass index (BMI) were found as significant covariates for CL and volume of distribution (V), respectively. The mean (relative standard error) estimates for CL and V of the final model were 0.419 L\/h (5.56%) and 29.50 (6.41%), respectively. IPV was 30.84% and the proportional RE was 6.44%. Internal validation demonstrated an acceptable predictive performance of the final model. A reliable population pharmacokinetic model was successfully developed, and it is the first enrolling real-life adults diagnosed with refractory epilepsy.<\/jats:p>","DOI":"10.3390\/pharmaceutics15061704","type":"journal-article","created":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T01:28:21Z","timestamp":1686533301000},"page":"1704","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Population Pharmacokinetic Analysis of Perampanel in Portuguese Patients Diagnosed with Refractory Epilepsy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7515-1204","authenticated-orcid":false,"given":"Rui","family":"Silva","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"CIBIT\/ICNAS\u2014Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Helena","family":"Colom","sequence":"additional","affiliation":[{"name":"Farmacoter\u00e0pia, Farmacogen\u00e8tica i Tecnologia Farmac\u00e8utica, IDIBELL\u2014Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Bellvitge, 08907 Hospitalet de Llobregat, Spain"},{"name":"Pharmacy and Pharmaceutical Technology and Physical Chemistry Department, Universitat de Barcelona, 08028 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7500-1671","authenticated-orcid":false,"given":"Joana","family":"Bicker","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"CIBIT\/ICNAS\u2014Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7394-3785","authenticated-orcid":false,"given":"Anabela","family":"Almeida","sequence":"additional","affiliation":[{"name":"CIBIT\/ICNAS\u2014Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"CIVG\u2014Vasco da Gama Research Center, EUVG\u2014Vasco da Gama University School, 3020-210 Coimbra, Portugal"}]},{"given":"Ana","family":"Silva","sequence":"additional","affiliation":[{"name":"Refractory Epilepsy Reference Centre, Centro Hospitalar e Universit\u00e1rio de Coimbra, EPE, 3004-561 Coimbra, Portugal"}]},{"given":"Francisco","family":"Sales","sequence":"additional","affiliation":[{"name":"Refractory Epilepsy Reference Centre, Centro Hospitalar e Universit\u00e1rio de Coimbra, EPE, 3004-561 Coimbra, Portugal"}]},{"given":"Isabel","family":"Santana","sequence":"additional","affiliation":[{"name":"Refractory Epilepsy Reference Centre, Centro Hospitalar e Universit\u00e1rio de Coimbra, EPE, 3004-561 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3854-6549","authenticated-orcid":false,"given":"Am\u00edlcar","family":"Falc\u00e3o","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"CIBIT\/ICNAS\u2014Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6981-6639","authenticated-orcid":false,"given":"Ana","family":"Fortuna","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"CIBIT\/ICNAS\u2014Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, 3000-548 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1111\/j.0013-9580.2005.66104.x","article-title":"Epileptic seizures and epilepsy: Definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE)","volume":"46","author":"Fisher","year":"2005","journal-title":"Epilepsia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1111\/epi.12550","article-title":"ILAE Official Report: A practical clinical definition of epilepsy","volume":"55","author":"Fisher","year":"2014","journal-title":"Epilepsia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/nrn1430","article-title":"The neurobiology of antiepileptic drugs","volume":"5","author":"Rogawski","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"107966","DOI":"10.1016\/j.neuropharm.2020.107966","article-title":"Mechanisms of action of currently used antiseizure drugs","volume":"168","author":"Sills","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.seizure.2010.10.027","article-title":"Antiepileptic drug therapy the story so far","volume":"19","author":"Brodie","year":"2010","journal-title":"Seizure Eur. J. Epilepsy"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1056\/NEJM200002033420503","article-title":"Early identification of refractory epilepsy","volume":"342","author":"Kwan","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1001\/jamaneurol.2017.3949","article-title":"Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs a 30-year longitudinal cohort study","volume":"75","author":"Chen","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1124\/pr.120.019539","article-title":"Drug resistance in epilepsy: Clinical impact, potential mechanisms, and new innovative treatment options","volume":"72","author":"Potschka","year":"2020","journal-title":"Pharmacol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"753753","DOI":"10.3389\/fneur.2021.753753","article-title":"New Trends and Most Promising Therapeutic Strategies for Epilepsy Treatment","volume":"12","author":"Riva","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1080\/17425255.2020.1724956","article-title":"Therapeutic drug monitoring of antiepileptic drugs: Current status and future prospects","volume":"16","author":"Johannessen","year":"2020","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1684\/epd.2016.0880","article-title":"Dosing strategies for antiepileptic drugs: From a standard dose for all to individualised treatment by implementation of therapeutic drug monitoring","volume":"18","author":"Landmark","year":"2016","journal-title":"Epileptic Disord."},{"key":"ref_12","unstructured":"IATDMCT, E.C. (2023, February 01). Definitions of TDM & CT. Available online: https:\/\/www.iatdmct.org\/about-us\/about-association\/about-definitions-tdm-ct.html."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1111\/imj.13412","article-title":"Individualised medicine: Why we need Bayesian dosing","volume":"47","author":"Donagher","year":"2017","journal-title":"Intern. Med. J."},{"key":"ref_14","first-page":"4","article-title":"Model-Informed Precision Dosing (MIPD)","volume":"14","author":"Lanao","year":"2022","journal-title":"Pharmaceutics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1111\/j.1528-1167.2008.01561.x","article-title":"Antiepileptic drugs\u2014Best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies","volume":"49","author":"Patsalos","year":"2008","journal-title":"Epilepsia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1097\/FTD.0000000000000546","article-title":"Therapeutic drug monitoring of antiepileptic drugs in epilepsy: A 2018 update","volume":"40","author":"Patsalos","year":"2018","journal-title":"Ther. Drug Monit."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1586\/14737175.8.6.929","article-title":"Value of therapeutic drug monitoring in epilepsy","volume":"8","author":"Johannessen","year":"2008","journal-title":"Expert Rev. Neurother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s40268-016-0148-6","article-title":"An Updated Overview on Therapeutic Drug Monitoring of Recent Antiepileptic Drugs","volume":"16","author":"Jacob","year":"2016","journal-title":"Drugs R&D"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/978-3-642-20195-0_3","article-title":"Principles of Therapeutic Drug Monitoring","volume":"205","author":"Zhao","year":"2011","journal-title":"Pediatr. Clin. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/bcp.14372","article-title":"Barriers and opportunities for the clinical implementation of therapeutic drug monitoring in oncology","volume":"87","author":"Menz","year":"2021","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1097\/FJC.0000000000000886","article-title":"Therapeutic Monitoring of Direct Oral Anticoagulants-Back to the Future?","volume":"76","author":"Hu","year":"2020","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1002\/cpt.593","article-title":"Scalpels not hammers: The way forward for precision drug prescription","volume":"101","author":"Neely","year":"2017","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/jcph.1633","article-title":"Parametric Approaches in Population Pharmacokinetics","volume":"62","author":"Guidi","year":"2022","journal-title":"J. Clin. Pharmacol."},{"key":"ref_24","unstructured":"European Medicines Agency FYCOMPA (2023, February 01). Summary of Product Characteristics. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/fycompa-epar-product-information_en.pdf."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1111\/epi.12240","article-title":"Concentration-effect relationships with perampanel in patients with pharmacoresistant partial-onset seizures","volume":"54","author":"Gidal","year":"2013","journal-title":"Epilepsia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"271","DOI":"10.2147\/DDDT.S154388","article-title":"Reference ranges for antiepileptic drugs revisited: A practical approach to establish national guidelines","volume":"12","author":"Reimers","year":"2018","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/epi.12865","article-title":"The clinical pharmacology profile of the new antiepileptic drug perampanel: A novel noncompetitive AMPA receptor antagonist","volume":"56","author":"Patsalos","year":"2015","journal-title":"Epilepsia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1111\/epi.13802","article-title":"Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non\u2013protein-bound concentrations","volume":"58","author":"Patsalos","year":"2017","journal-title":"Epilepsia"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.eplepsyres.2016.08.025","article-title":"Pharmacokinetics, exposure\u2013cognition, and exposure\u2013efficacy relationships of perampanel in adolescents with inadequately controlled partial-onset seizures","volume":"127","author":"Villanueva","year":"2016","journal-title":"Epilepsy Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1111\/ane.12874","article-title":"Pharmacokinetic\/pharmacodynamic analysis of adjunctive perampanel in subjects with partial-onset seizures","volume":"137","author":"Takenaka","year":"2018","journal-title":"Acta Neurol. Scand."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S1474-4422(09)70304-7","article-title":"Definition of refractory epilepsy: Defining the indefinable?","volume":"9","author":"Kwan","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1111\/bcp.13647","article-title":"Comparison of the Cockcroft\u2013Gault, MDRD and CKD-EPI equations for estimating ganciclovir clearance","volume":"84","year":"2018","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"122491","DOI":"10.1016\/j.jchromb.2020.122491","article-title":"Development and application of an HPLC-DAD technique for human plasma concentration monitoring of perampanel and lamotrigine in drug-resistant epileptic patients","volume":"1162","author":"Bicker","year":"2021","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/BF01117450","article-title":"Application of Akaike\u2019s Information Criterion (AIC) in the Evaluation of Linear Pharmacokinetic Equations","volume":"6","author":"Yamaoka","year":"1978","journal-title":"J. Pharmacokinet. Biopharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"71","DOI":"10.12688\/f1000research.2-71.v2","article-title":"Using Akaike\u2019s information theoretic criterion in mixed-effects modeling of pharmacokinetic data: A simulation study [version 2; peer review: 1 approved, 1 approved with reservations, 1 not approved]","volume":"2","author":"Olofsen","year":"2014","journal-title":"F1000Research"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1208\/s12248-009-9133-0","article-title":"Importance of shrinkage in empirical bayes estimates for diagnostics: Problems and solutions","volume":"11","author":"Savic","year":"2009","journal-title":"AAPS J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1023\/A:1016215116835","article-title":"Population Pharmacokinetic Modeling: The Importance of Informative Graphics","volume":"12","author":"Ette","year":"1995","journal-title":"Pharm. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1038\/sj.clpt.6100241","article-title":"Diagnosing Model Diagnostics","volume":"82","author":"Karlsson","year":"2007","journal-title":"Clin. Pharm. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1208\/s12248-011-9255-z","article-title":"Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models","volume":"13","author":"Bergstrand","year":"2011","journal-title":"AAPS J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1002\/j.1552-4604.1997.tb04326.x","article-title":"Stability and performance of a population pharmacokinetic model","volume":"37","author":"Ette","year":"1997","journal-title":"J. Clin. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1177\/0091270003253624","article-title":"Model appropriateness and population pharmacokinetic modeling","volume":"43","author":"Ette","year":"2003","journal-title":"J. Clin. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1214\/aos\/1176344552","article-title":"Bootstrap methods: Another look at the jackknife","volume":"7","author":"Efron","year":"1979","journal-title":"Ann. Stat."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e060326","DOI":"10.1136\/bmjopen-2021-060326","article-title":"The current understanding of precision medicine and personalised medicine in selected research disciplines: Study protocol of a systematic concept analysis","volume":"12","author":"Parkinson","year":"2022","journal-title":"BMJ Open"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1002\/psp4.12353","article-title":"Model-Informed Precision Dosing at the Bedside: Scientific Challenges and Opportunities","volume":"7","author":"Keizer","year":"2018","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1097\/FTD.0000000000000274","article-title":"Perampanel Serum Concentrations in Adults With Epilepsy: Effect of Dose, Age, Sex, and Concomitant Anti-epileptic Drugs","volume":"38","author":"Patsalos","year":"2016","journal-title":"Ther. Drug Monit."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1080\/17425255.2019.1560420","article-title":"Pharmacokinetic and pharmacodynamic considerations for the clinical efficacy of perampanel in focal onset seizures","volume":"15","author":"Gigli","year":"2019","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"105389","DOI":"10.1016\/j.tiv.2022.105389","article-title":"Study of the metabolic stability profiles of perampanel, rufinamide and stiripentol and prediction of drug interactions using HepaRG cells as an in vitro human model","volume":"82","author":"Meirinho","year":"2022","journal-title":"Toxicol. Vitr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1093\/chromsci\/bmaa060","article-title":"Quantification of the Plasma Concentrations of Perampanel Using High-Performance Liquid Chromatography and Effects of the CYP3A4* 1G Polymorphism in Japanese Patients","volume":"58","author":"Ohkubo","year":"2020","journal-title":"J. Chromatogr. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1097\/FTD.0000000000000416","article-title":"Therapeutic Drug Monitoring for Perampanel in Japanese Epilepsy Patients: Influence of Concomitant Antiepileptic Drugs","volume":"39","author":"Yamamoto","year":"2017","journal-title":"Ther. Drug Monit."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Grze\u015bk, G., Stolarek, W., Kasprzak, M., Grze\u015bk, E., Rogowicz, D., Wici\u0144ski, M., and Krzy\u017canowski, M. (2021). Therapeutic drug monitoring of carbamazepine: A 20-year observational study. J. Clin. Med., 10.","DOI":"10.3390\/jcm10225396"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3973","DOI":"10.1016\/j.clnu.2021.04.033","article-title":"Body composition assessment using bioelectrical impedance analysis (BIA) in a wide cohort of patients affected with mild to severe obesity","volume":"40","author":"Brunani","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1212\/WNL.0000000000001558","article-title":"Perampanel efficacy and tolerability with enzyme-inducing AEDs in patients with epilepsy","volume":"12","author":"Gidal","year":"2015","journal-title":"Neurology"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/6\/1704\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:52:17Z","timestamp":1760125937000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/6\/1704"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,10]]},"references-count":52,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["pharmaceutics15061704"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15061704","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2023,6,10]]}}}