Intraocular drugs: pharmacokinetic strategies and the influence on efficacy and durability.

INTRODUCTION The modern treatment of chorioretinal vascular diseases follows the recent development and rapid adoption of drugs that inhibit vascular endothelial growth factor (VEGF). All anti-VEGF drugs are delivered intravitreally, with clinical behavior, including efficacy, durability, and safety, largely determined by their pharmacokinetic properties. AREAS COVERED Properties of these new drugs include additional binding targets (placental growth factor (PlGF) and angiopoietin 2 (Ang 2)), binding affinity, potency, intravitreal half-life, and increased molar dose. A PubMed search for 'pharmacokinetics of anti-VEGF drugs' was performed from 2000 to 2023. Relevant studies were reviewed and referred to in the manuscript. EXPERT OPINION Early developers concentrated on improving efficacy, but since maximum efficacy with VEGF inhibition has been reached, development has pivoted to extending the duration of action. Durability strategies include inhibiting additional pathways (faricimab), increasing molar dose (abicipar, brolucizumab, faricimab, and aflibercept 8 mg), and prolonging the intravitreal half-life (abicipar and KSI-301). Recent phase 3 trials demonstrated modest improvements in durability, but failures that might be attributed to these strategies (conjugation and manufacturing processes) have occurred. Future drug development focuses on extending duration of action with implantable reservoirs (ranibizumab port delivery system), sustained release devices (tyrosine kinase inhibitors), and gene therapy.