{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T05:17:17Z","timestamp":1788585437932,"version":"build-2803163510"},"reference-count":114,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Intravitreal inhibition of vascular endothelial growth factor (VEGF) has transformed the management of neovascular age-related macular degeneration, diabetic macular oedema and macular oedema secondary to retinal vein occlusion, but frequent monitoring and retreatment remain major burdens. Ocular half-life is often used as shorthand for durability, although the clinical interval is produced by a wider molecular and biological system. This narrative review examines how dose, molecular format, hydrodynamic size, binding affinity, valency, ligand spectrum, target turnover, tissue distribution and delivery architecture determine the time for which an eye remains controlled. Human ocular pharmacokinetic and pharmacodynamic evidence is interpreted according to compartment, assay and model provenance, with particular attention to the distinction between drug elimination, free-ligand suppression, anatomical control and protocol-assigned treatment interval. Trial evidence for ranibizumab, aflibercept, conbercept, brolucizumab and faricimab shows that extended dosing can arise from greater starting exposure, altered binding architecture or pathway expansion without a proportionate change in intrinsic ocular half-life. Patient phenotype and retreatment rules further modify the observed interval. Refillable reservoirs, biodegradable depots and ocular gene therapy change the governing kinetics from bolus elimination to controlled release or sustained local production, thereby increasing the importance of reversibility and cumulative safety. We propose that durability be defined as a time-to-threshold phenotype integrating active target-site exposure, biological demand, anatomical recurrence, all treatment-related procedures and safety. Standardised estimands, longitudinal human ocular sampling, spatial exposure methods and externally validated mechanism-informed models are needed to make molecular durability comparable and clinically actionable.<\/jats:p>","DOI":"10.3390\/ijms27177786","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:48:36Z","timestamp":1788256116000},"page":"7786","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Determinants of Intravitreal Anti-VEGF Durability: Drug Architecture, Intraocular Pharmacokinetics, Target Biology and Treatment Resistance"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8399-7456","authenticated-orcid":false,"given":"Georgios D.","family":"Panos","sequence":"first","affiliation":[{"name":"Division of Ophthalmology and Visual Sciences, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK"},{"name":"First Department of Ophthalmology, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo","family":"Empeslidis","sequence":"additional","affiliation":[{"name":"Vantage Biosciences Ltd., London SW1Y 5ES, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7071-1557","authenticated-orcid":false,"given":"Efstratia","family":"Amaxilati","sequence":"additional","affiliation":[{"name":"First Department of Ophthalmology, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2441-545X","authenticated-orcid":false,"given":"Georgios N.","family":"Tsiropoulos","sequence":"additional","affiliation":[{"name":"First Department of Ophthalmology, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Topouzis","sequence":"additional","affiliation":[{"name":"First Department of Ophthalmology, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis A.G.","family":"Konstas","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4283-5260","authenticated-orcid":false,"given":"Eleftherios","family":"Chatzimichail","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Basel, 4056 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zisis","family":"Gatzioufas","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Basel, 4056 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winfried","family":"Amoaku","sequence":"additional","affiliation":[{"name":"Division of Ophthalmology and Visual Sciences, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1056\/NEJMoa054481","article-title":"Ranibizumab for neovascular age-related macular degeneration","volume":"355","author":"Rosenfeld","year":"2006","journal-title":"N. 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