Pharmacokinetics and ocular tissue penetration of VEGF trap after intravitreal injection in rabbits

Abstract Purpose VEGF Trap is a potent antiangiogenic agent that binds and blocks the action of all VEGF‐A isoforms and placental growth factor and, is active in numerous animal models of age‐related ocular neovascularization and diabetic retinopathy, when administered either intravitreally or systemically. Moreover, systemic administration of VEGF Trap was active in reducing excess retinal thickness in a Phase I study in age‐related macular edema. To understand the pharmacokinetics following intravitreal administration, VEGF Trap (500 mcg) was administered to both eyes of pigmented rabbits. Methods Plasma and eyes were harvested from three animals/time point at defined times to 4 weeks after administration. Concentrations of VEGF Trap, free and bound to VEGF, were determined in plasma, vitreous, choroid, and retina by ELISA. Results Maximal vitreal concentrations of free VEGF Trap were approximately 500 mcg/mL at 0.25 to 6 hours after injection. The drug was cleared from the vitreous in a first order process with a half‐life of approximately 4.5 days. Vitreal VEGF:VEGF Trap complex reached a plarteau of 0.6 mcg/mL 10 days after administration. Drug was detected in both retina and choroid, and the elimination profile from these tissues approximated by that of the vitreous. Peak plasma total drug concentrations of 1.6 mcg/mL occurred at 10 days. At 4 weeks, the vitreal free VEGF Trap remained over 10‐fold in excess of bound VEGF Trap and the complex levels were on a plateau. Conclusion Given the vitreal half‐life, free should remain in excess of bound for at least 3 additional half‐lives (13.5 days), suggesting that eye VEGF production would be completely blocked for more than 6 weeks after adminstration of of 500 mcg/eye of VEGF Trap. Commercial interest