April 2009
Volume 50, Issue 13
ARVO Annual Meeting Abstract  |   April 2009
A Multi-Targeted Receptor Tyrosine Kinase Inhibitor for the Treatment of Neovascular AMD: Preclinical Support of Clinical Development of Pazopanib Eye Drops
Author Affiliations & Notes
  • C. E. Fishman
    Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania
  • T. K. Hart
    Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania
  • Footnotes
    Commercial Relationships  C.E. Fishman, GlaxoSmithKline, E; T.K. Hart, GlaxoSmithKline, E.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science April 2009, Vol.50, 5005. doi:
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      C. E. Fishman, T. K. Hart; A Multi-Targeted Receptor Tyrosine Kinase Inhibitor for the Treatment of Neovascular AMD: Preclinical Support of Clinical Development of Pazopanib Eye Drops. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5005.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : To outline the scope of preclinical testing to support clinical trials of Pazopanib eye drops in human volunteers for up to 2 weeks and in AMD patients for one month, with an extension period of up to 6 months total administration.

Methods: : Pazopanib (GW786034) is under clinical development to treat cancer in an oral form and neovascular age-dependent macular degeneration (AMD) in an eye drop formulation. Pazopanib targets the vascular endothelial growth factor receptors -1, 2, and 3, platelet-derived growth factor receptor - and -β, and the stem cell factor receptor (c-kit). In support of the oral program for cancer, the preclinical toxicology package included oral toxicity studies of up to 6 months in rats and up to 1 year in monkeys, as well as genotoxicity, safety pharmacology and reproductive toxicity studies. To support testing of eye drops in humans for up to 1 month, additional ocular toxicity studies were conducted in dogs and rabbits for up to 1 month. In these studies, 60 uL of the identical clinical formulations (concentrations of 0, 2 and 5 mg/mL Pazopanib) were administered 6 times daily into one eye. Irritation scoring by Draize technique was performed pre and post dosing, daily for the first week and twice weekly thereafter. Ophthalmic examination by a board certified veterinary ophthalmologist was performed on Study day 2 and approximately weekly thereafter, including IOP, indirect fundoscopy, slit lamp biomicroscopy and evaluation of ocular adnexae. Histopathology of ocular structures was performed at study termination. Extension of clinical dosing of eye drops for up to 6 months in AMD patients was further supported by interim analyses of a 6 month ocular toxicity study in dogs, that included bilateral ocular dosing, rigorous assessment of ocular and systemic endpoints and ocular histopathology.

Results: : No ocular effects were identified in any of the oral toxicity studies and there was no significant local toxicity in the ocular studies in either species. Systemic exposures following eye drop dosing were very low relative to systemic administration in both species.

Conclusions: : Results of oral and ocular toxicity studies support a high degree of ocular safety with low systemic exposure of pazopanib eye drops.

Keywords: age-related macular degeneration • drug toxicity/drug effects • clinical research methodology 

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