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 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 microg x 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.


CONCLUSIONS
Pazopanib may be useful for treatment of CNV in humans.
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
Kyoichi
K
Takahashi
Yoshitsugu
Y
Saishin
Yumiko
Y
Saishin
Andrew G
AG
King
Robert
R
Levin
Peter A
PA
Campochiaro
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D001682:Biological Availability; D002829:Choroid / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000503:physiopathology / Q000517:prevention & control*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007191:Indazoles; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012160:Retina / Q000378:metabolism; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution
D020533:Angiogenesis Inhibitors; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib