Mathematical Models of Topically and Intravitreally Applied Ranibizumab.

Purpose: Wet age-related macular degeneration (AMD) causes vision loss when vascular endothelial growth factor (VEGF) stimulates blood vessel growth into the light-sensitive retina. Anti-VEGF treatments such as ranibizumab are currently administered to treat wet AMD via intravitreal injections, which are unpleasant, expensive, and risk complications. We explored the efficacy of topically administered ranibizumab, with cell-penetrating peptides (CPPs). Methods: Ex vivo pig eyes were divided into three groups and treated with (1) topical or (2) intravitreal ranibizumab and CPP, or (3) intravitreal ranibizumab. ELISAs measured ranibizumab and VEGF concentrations in the aqueous and vitreous at 20 min, 40 min, 1 h, and 3.5 h (n = 3, per group). An ordinary differential equation model was formulated to describe the evolving concentrations of ranibizumab, VEGF, and their compounds in the tear, aqueous, and vitreal compartments. Results: Experimental-Topical: aqueous ranibizumab levels increased significantly, coincident with a significant drop in aqueous VEGF. Vitreal ranibizumab increased significantly, while vitreal VEGF remained constant. Intravitreal (with and without CPP): vitreal ranibizumab reached high concentrations, coincident with a significant drop in vitreal VEGF. Mathematical-topical treatment may provide sustained, moderate suppression of vitreal VEGF levels, while intravitreal treatment provides strong suppression, which lessens between treatments. Conclusions: CPP allows topical ranibizumab to penetrate the cornea. Combined intravitreal/topical treatment presents a promising approach; topical treatment suppresses vitreal VEGF levels between injections and thereby potentially reduces the frequency of injections. Treatment efficacy would be enhanced if ranibizumab's rate of binding to VEGF or tear residence time could be increased.