{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T19:47:14Z","timestamp":1782244034575,"version":"3.54.5"},"reference-count":46,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Provincial Secretariat for Higher Education and Scientific Research, AP Vojvodina, Republic of Serbia","award":["003794555 2025 09418 003 000 000 001 04 002"],"award-info":[{"award-number":["003794555 2025 09418 003 000 000 001 04 002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biosensors"],"abstract":"<jats:p>Epilepsy can be effectively controlled with appropriately selected antiepileptic drugs and carefully titrated dosage regimens. Although lamotrigine exhibits favorable pharmacokinetic properties following oral administration, fluctuations in plasma concentration may still occur due to interindividual variability, irregular dosing, and pharmacokinetic interactions. In this study, a subcutaneous implant capable of monitoring plasma lamotrigine levels and adjusting drug delivery accordingly was developed to maintain stable therapeutic concentrations. The proposed system combines intermittent drug release with continuous concentration monitoring using an enzymatic biosensor. A pharmacokinetic model based on first-order absorption and elimination kinetics was implemented in MATLAB\/Simulink using clinical lamotrigine concentration data obtained from patients receiving chronic therapy. In the closed-loop configuration, biosensor measurements were used as feedback for a proportional\u2013integral (PI) controller that adjusted the implant release rate in real time. System performance was evaluated using in silico simulations. The open-loop system produced rapid concentration peaks (Cmax \u2248 0.06 mmol\/L) followed by a decline below the therapeutic threshold within approximately 80 min. In contrast, the closed-loop system achieved lower peak concentrations (Cmax \u2248 0.045 mmol\/L) and maintained plasma concentrations within the therapeutic range of 0.02\u20130.03 mmol\/L with reduced fluctuations. These findings support further investigation of biosensor-guided closed-loop lamotrigine delivery systems.<\/jats:p>","DOI":"10.3390\/bios16060348","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T18:35:05Z","timestamp":1782239705000},"page":"348","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design and Simulation of Lamotrigine Intermittent Release from a Subcutaneous Implant with an Enzymatic Biosensor Based on Clinical Data"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0225-515X","authenticated-orcid":false,"given":"Jovana","family":"Arsenovi\u0107","sequence":"first","affiliation":[{"name":"Department of Computing and Control Engineering, Faculty of Technical Sciences, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa","family":"Budak","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melinda","family":"Ta\u0161i","sequence":"additional","affiliation":[{"name":"Department of Computing and Control Engineering, Faculty of Technical Sciences, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8354-3868","authenticated-orcid":false,"given":"Mladena","family":"Lali\u0107-Popovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nemanja","family":"Todorovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4082-5480","authenticated-orcid":false,"given":"Maja","family":"Milanovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8595-6065","authenticated-orcid":false,"given":"Nata\u0161a","family":"Mili\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5286-3858","authenticated-orcid":false,"given":"Nata\u0161a","family":"Milo\u0161evi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Xue, J., Li, X., Zhao, Y., Jia, W., Wu, X., Jiang, S., and Ding, J. (2025). Global, regional, and national burden of idiopathic epilepsy in older adults, 1990\u20132021: A systematic analysis for the Global Burden of Disease Study 2021. BMC Med., 23.","DOI":"10.1186\/s12916-025-04268-8"},{"key":"ref_2","unstructured":"GBD Epilepsy Collaborators (2025). Global, regional, and national burden of epilepsy, 1990\u20132021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet Public Health, 10, e203\u2013e227."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Shan, T., Zhu, Y., Fan, H., Liu, Z., Xie, J., Li, M., and Jing, S. (2024). Global, regional, and national time trends in the burden of epilepsy, 1990\u20132019: An age-period-cohort analysis for the global burden of disease 2019 study. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1418926"},{"key":"ref_4","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_5","unstructured":"(2026, May 10). Who.int [Homepage on the Internet]. Geneva: World Health Organization. Available online: https:\/\/www.who.int\/."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1055\/s-0038-1646947","article-title":"Global Health: Epilepsy","volume":"38","author":"Ali","year":"2018","journal-title":"Semin. Neurol."},{"key":"ref_7","first-page":"87","article-title":"Epilepsy: Treatment Options","volume":"96","author":"Liu","year":"2017","journal-title":"Am. Fam. Physician"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e36","DOI":"10.3928\/00904481-20150203-10","article-title":"Antiepileptic drugs\u2014A review","volume":"44","author":"Sankaraneni","year":"2015","journal-title":"Pediatr. Ann."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/S1474-4422(12)70153-9","article-title":"Adverse effects of antiepileptic drugs","volume":"11","author":"Perucca","year":"2012","journal-title":"Lancet 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","unstructured":"(2026, May 10). Ema.europa.eu [Homepage on the Internet]. Amsterdam: European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/homepage."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1097\/FPC.0000000000000397","article-title":"PharmGKB summary: Lamotrigine pathway, pharmacokinetics and pharmacodynamics","volume":"30","author":"Callisto","year":"2020","journal-title":"Pharmacogenet. Genom."},{"key":"ref_13","unstructured":"(2025, December 20). FDA.gov [Homepage on the Internet]. Maryland: United States Government, Available online: https:\/\/www.fda.gov\/."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"433","DOI":"10.2165\/00003088-199325060-00003","article-title":"Lamotrigine clinical pharmacokinetics","volume":"25","author":"Rambeck","year":"1993","journal-title":"Clin. Pharmacokinet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/B978-0-12-397220-0.00006-4","article-title":"Lamotrigine","volume":"37","author":"Beattie","year":"2012","journal-title":"Profiles Drug Subst. Excip. Relat. Methodol."},{"key":"ref_16","first-page":"1","article-title":"Introduction to biosensors","volume":"60","author":"Bhalla","year":"2016","journal-title":"Essays Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0956-5663(01)00115-4","article-title":"Electrochemical biosensors: Recommended definitions and classification","volume":"16","author":"Toth","year":"2001","journal-title":"Biosens. Bioelectron."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Polat, E.O., Cetin, M.M., Tabak, A.F., Bilget G\u00fcven, E., Uysal, B.\u00d6., Arsan, T., Kabbani, A., Hamed, H., and G\u00fcl, S.B. (2022). Transducer Technologies for Biosensors and Their Wearable Applications. Biosensors, 12.","DOI":"10.3390\/bios12060385"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/BF03191157","article-title":"Lamotrigine and valproate pharmacokinetics interactions in epileptic patients","volume":"34","author":"Lalic","year":"2009","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1097\/ALN.0000000000001687","article-title":"Calculating Ideal Body Weight: Keep It Simple","volume":"127","author":"Moreault","year":"2017","journal-title":"Anesthesiology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2290","DOI":"10.1016\/j.compchemeng.2005.05.014","article-title":"Modelling and control of drug delivery systems","volume":"29","author":"Dua","year":"2005","journal-title":"Comput. Chem. Eng."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"20","DOI":"10.3390\/s40400020","article-title":"Mathematical Model of the Biosensors Acting in a Trigger Mode","volume":"4","author":"Baronas","year":"2004","journal-title":"Sensors"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/S0022-3565(24)36662-5","article-title":"Interindividual variability in expression and activity of human beta-glucuronidase in liver and kidney: Consequences for drug metabolism","volume":"281","author":"Sperker","year":"1997","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D750","DOI":"10.1093\/nar\/gkp889","article-title":"BioNumbers\u2014The database of key numbers in molecular and cell biology","volume":"38","author":"Milo","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bse0590001","article-title":"Enzymes: Principles and biotechnological applications","volume":"59","author":"Robinson","year":"2015","journal-title":"Essays Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/bcp.12984","article-title":"Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: Influence of polymorphism of UDP-glucuronosyltransferases and drug transporters","volume":"82","author":"Milosheska","year":"2016","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_27","first-page":"25","article-title":"A systematic review of population pharmacokinetics of lamotrigine","volume":"140","author":"Methaneethorn","year":"2018","journal-title":"Epilepsy Res."},{"key":"ref_28","unstructured":"Popovi\u0107, J., Milo\u0161evi\u0107, N., and Popovi\u0107, K. (2021). Dvokompartmanski otvoreni model. Farmakokinetika, Medicinski Fakultet."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Vilanova, R., and Visioli, A. (2012). The SIMC Method for Smooth PID Controller Tuning. PID Control in the Third Millennium. Advances in Industrial Control, Springer.","DOI":"10.1007\/978-1-4471-2425-2"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e12400","DOI":"10.1002\/jev2.12400","article-title":"A beginner\u2019s guide to study extracellular vesicles in human blood plasma and serum","volume":"13","author":"Nieuwland","year":"2024","journal-title":"J. Extracell. Vesicles"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1212\/01.WNL.0000138424.33979.0C","article-title":"Correlating lamotrigine serum concentrations with tolerability in patients with epilepsy","volume":"63","author":"Hirsch","year":"2004","journal-title":"Neurology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1177\/2045125316672573","article-title":"Variation in dose and plasma level of lamotrigine in patients discharged from a mental health trust","volume":"7","author":"Dzahini","year":"2017","journal-title":"Ther. Adv. Psychopharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/j.1600-0404.2005.00505.x","article-title":"New antiepileptic drugs in practice\u2014How do they perform in the real world?","volume":"181","author":"Sander","year":"2005","journal-title":"Acta Neurol. Scand. Suppl."},{"key":"ref_34","first-page":"249","article-title":"A case of lamotrigine-associated anticonvulsant hypersensitivity syndrome","volume":"10","author":"Blondin","year":"2008","journal-title":"Prim. Care Companion J. Clin. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101559","DOI":"10.1016\/j.smrv.2021.101559","article-title":"Effects of anti-seizure medications on sleep architecture and daytime sleepiness in patients with epilepsy: A literature review","volume":"60","author":"Liguori","year":"2021","journal-title":"Sleep Med. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1080\/15563650.2017.1370096","article-title":"Acute lamotrigine overdose: A systematic review of published adult and pediatric cases","volume":"56","author":"Alyahya","year":"2018","journal-title":"Clin. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"106408","DOI":"10.1016\/j.eplepsyres.2020.106408","article-title":"Comparison of long-term efficacy, tolerability, and safety of oxcarbazepine, lamotrigine, and levetiracetam in patients with newly diagnosed focal epilepsy: An observational study in the real world","volume":"166","author":"Li","year":"2020","journal-title":"Epilepsy Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1111\/j.1528-1157.2000.tb00165.x","article-title":"Prognostic factors affecting long-term retention of topiramate in patients with chronic epilepsy","volume":"41","author":"Lhatoo","year":"2000","journal-title":"Epilepsia"},{"key":"ref_39","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_40","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1016\/j.xphs.2018.01.007","article-title":"Challenges and Opportunities for the Subcutaneous Delivery of Therapeutic Proteins","volume":"107","author":"Turner","year":"2018","journal-title":"J. Pharm. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"122125","DOI":"10.1016\/j.ijpharm.2022.122125","article-title":"Transport and distribution of biotherapeutics in different tissue layers after subcutaneous injection","volume":"626","author":"Rahimi","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Rocchitta, G., Spanu, A., Babudieri, S., Latte, G., Madeddu, G., Galleri, G., Nuvoli, S., Bagella, P., Demartis, M.I., and Fiore, V. (2016). Enzyme Biosensors for Biomedical Applications: Strategies for Safeguarding Analytical Performances in Biological Fluids. Sensors, 16.","DOI":"10.3390\/s16060780"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Campuzano, S., Pedrero, M., Y\u00e1\u00f1ez-Sede\u00f1o, P., and Pingarr\u00f3n, J.M. (2019). Antifouling (Bio)materials for Electrochemical (Bio)sensing. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20020423"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Alizadeh, N., Georgas, A., Argirusis, C., Sourkouni, G., and Argirusis, N. (2026). Polymer Coatings for Electrochemical Biosensors. Coatings, 16.","DOI":"10.3390\/coatings16020164"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Xu, J., and Lee, H. (2020). Anti-Biofouling Strategies for Long-Term Continuous Use of Implantable Biosensors. Chemosensors, 8.","DOI":"10.3390\/chemosensors8030066"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"113242","DOI":"10.1016\/j.bios.2021.113242","article-title":"Biomimetic electrochemical sensors: New horizons and challenges in biosensing applications","volume":"185","author":"Romanholo","year":"2021","journal-title":"Biosens. Bioelectron."}],"container-title":["Biosensors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6374\/16\/6\/348\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T18:57:31Z","timestamp":1782241051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6374\/16\/6\/348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,21]]},"references-count":46,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["bios16060348"],"URL":"https:\/\/doi.org\/10.3390\/bios16060348","relation":{},"ISSN":["2079-6374"],"issn-type":[{"value":"2079-6374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,21]]}}}