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Y. Saishin, K. Takahashi, Y. Saishin, A. King, R. Levin, P. A. Campochiaro; Oral Administration of the VEGF Receptor Kinase Inhibitor Pazopanib Causes Suppression and Regression of Choroidal Neovascularization in Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3439. doi: https://doi.org/.
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Pazopanib is a potent multi-targeted tyrosine kinase inhibitor that blocks ligand-induced activation of VEGF, PDGF, c-kit (SCF) receptors. In this study, we sought to investigate the potential of pazopanib for treatment of choroidal neovascularization (CNV).
We tested the ability of orally administered pazopanib to prevent or to cause regression of CNV in the murine model of laser-induced CNV and investigated pharmacokinetics in mice.
Twice a day administration of 100 mg/kg (200 mg/kg/day) of pazopanib by gavage starting the day of laser-induce rupture of Bruch’s membrane reduced the area of CNV by 93% at day 14 (p=0.0001 by linear mixed model). To determine if pazopanib affected pre-existent CNV, mice had rupture of Bruch’s membrane and the baseline amount of CNV was measured at day 7 (0.957±0.100 x 10-2 mm2). The remainder of the mice were treated twice a day by gavage with 8, 40, or 200 mg/kg/day of pazopanib or vehicle. At day 14, CNV areas in 10-2 mm2 were 1.912±0.133 in vehicle-treated mice and 1.097±0.090, 0.400±0.053, and 0.280±0.036 in mice treated with 8, 40, or 200 mg/kg/day of pazopanib. Thus treatment with 40 or 200 mg/kg/day of pazopanib resulted in regression of 58% and 71% regression of the CNV between 7 and 14 days (p≤0.0013). Single dose pharmacokinetics of pazopanib given by gavage in hydroxypropyl methylcellulose with 0.1% Tween:Table1Additional studies demonstrated that orally administered pazopanib resulted in dose related drug levels in the target tissues (retina/choroid) in these mice.
The oral pharmacokinetic properties of pazopanib were consistent with good bioavailability in mice. Pazopanib strongly suppressed CNV and caused substantial regression of CNV that has been present for one week. These data suggest pazopanib may be useful to treat disease involving aberrant ocular neovascularization.
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