Abstract
Abstract: :
Ranibizumab (LucentisTM) is an anti–VEGF (vascular endothelial growth factor) antibody fragment being developed for the potential treatment of the wet form of age–related macular degeneration (AMD). Ranibizumab binds to VEGF, thus blocking its ability to induce blood vessel growth beneath the retina, as well as blood vessel leakiness, which leads to wet AMD disease progression. Ranibizumab is currently administered by intravitreal (ITV) injection. Purpose: This study investigated the pharmacokinetics of ranibizumab following administration by subconjunctival, intracameral, and ITV routes to compare relative drug exposure within the eye and systemic circulation. Methods: Ranibizumab was administered to four groups of New Zealand White rabbits (72 animals) as follows: 1) 500 µg/eye, subconjunctival (SCJ) administration; 2) 500 µg/eye, intracameral administration; 3) 500 µg/eye, intravitreal administration; 4) 4000 µg/eye, SCJ administration. Three rabbits were used per group, per timepoint, with timepoints ranging from 4 hours to 11 days after administration (five to seven timepoints per group). Serum samples were collected for all animals at four hours post–dose; serum, aqueous humor, vitreal humor and retinal tissue samples were obtained at termination. In all matrices, ranibizumab concentration was determined by ELISA. Pharmacokinetic analysis was performed using noncompartmental methods. Results: The highest serum concentrations of ranibizumab were detected in the SCJ groups, with the greatest levels for the administration of 4000 µg/eye. Ranibizumab was also detected in the serum after intracameral and ITV administration. The highest levels of ranibizumab in the aqueous humor were detected for ITV administration, and ranibizumab was detected in the aqueous humor for other routes as well. Ranibizumab was detected in the vitreous humor for all routes, with the highest levels observed for ITV, and with detection at 11 days for ITV and SCJ administration. Conclusions: Ranibizumab was detected in the vitreous humor out to 11 days following subconjunctival administration of 4000 µg/eye. This demonstrates that extraocular administration can provide exposure in the vitreous body, supporting further investigation of extraocular routes of administration for this drug.
Keywords: pharmacology • age–related macular degeneration • vitreous