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Suppression and Regression of Choroidal Neovascularization by the Multitargeted Kinase Inhibitor Pazopanib
Kyoichi Takahashi, MD, PhD;
Yoshitsugu Saishin, MD, PhD;
Yumiko Saishin, MD, PhD;
Andrew G. King, PhD;
Robert Levin, PhD;
Peter A. Campochiaro, MD
Arch Ophthalmol. 2009;127(4):494-499.
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 photocoagulation. 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 pazopanib. A single oral dose of 4 or 100 mg/kg resulted in an area under the curve from time 0 to the last quantifiable 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.
Author Affiliations: Departments of Ophthalmology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland (Drs Takahashi, Yoshitsugu Saishin, Yumiko Saishin, and Campochiaro); and Cancer Research, GlaxoSmithKline, Collegeville, Pennsylvania (Drs King and Levin).
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