Suppression and regression of choroidal neovascularization by the multitargeted kinase inhibitor pazopanib

Objective: To investigate pazopanib hydrochloride, a multitargeted kinase inhibitor, for treatment of choroidal neovascularization (CNV). Methods: Choroidal neovascularization was induced in mice by rupture of Bruch membrane with laser photoco- agulation. Mice were treated with pazopanib by gavage or periocular injection, and the area of CNV was measured. Results: Twice-daily gavage of pazopanib, 100 mg/kg, suppressed the development of CNV by 93%. Treatment of established CNV between days 7 and 14 with 8, 40, or 200 mg/kg per day reduced CNV by 0%, 58%, and 71%, respectively. Substantial regression (40%) of CNV was also achieved after periocular injection of pazo- panib. A single oral dose of 4 or 100 mg/kg resulted in an area under the curve from time 0 to the last quanti-fiable concentration of 129.6 and 752.0 μg · h/mL, respectively. After 7 days of 4, 20, or 100 mg/kg twice a day by gavage, plasma levels were 1300, 4900, and 5800 ng/mL and levels in the retina/choroid were 4800, 28 800, and 38 000 ng/g of tissue. Conclusions: Orally administered pazopanib has good bioavailability to the retina/choroid and strongly suppresses CNV in mice. Treatment with pazopanib after CNV is established causes dose-dependent regression of CNV. Clinical Relevance: Pazopanib may be useful for treatment of CNV in humans.