A Multi-Targeted Receptor Tyrosine Kinase Inhibitor for the Treatment of Neovascular AMD: Results of a Healthy Volunteer Safety and Tolerability Study of Pazopanib Eye Drops

Abstract

Purpose: : Pazopanib (GW786034) is a potent multi-targeted receptor tyrosine kinase inhibitor under clinical development for the treatment of age-related macular degeneration (via topical ophthalmic administration) and several cancers (via oral administration). 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). Pazopanib has shown significant activity in nonclinical models of tumor angiogenesis and ocular neovascularization. A study to evaluate the safety and tolerability of pazopanib eye drops in healthy volunteers is described.

Methods: : A single-masked, placebo-controlled, randomized dose-rising study evaluated local and systemic safety, tolerability and systemic pharmacokinetics of pazopanib ophthalmic solution (2 mg/mL and 5 mg/mL) following single and repeat topical dosing (three times daily for 14 days) in healthy subjects. Pazopanib or placebo was randomly assigned to one eye only and artificial tear control (comparator control) was assigned to the contralateral eye.

Results: : Data indicate that ocular administration of pazopanib solution at 2 mg/mL and 5 mg/mL was generally well-tolerated compared to placebo and comparator control. There were no clinically significant changes in results of ophthalmic examinations. At 5 mg/ml, transient moderate stinging was reported. Systemic exposure was low but detectable in all subjects receiving pazopanib eye drops.

Conclusions: : Ocular administration of pazopanib solution at 2 mg/mL and 5 mg/mL up to three times daily for 14 days was well tolerated and the absence of safety signals has led to the development of an ongoing Proof of Concept Study in neovascular AMD patients.

Clinical Trial: : www.clinicaltrials.gov NCT00463320

Keywords: age-related macular degeneration • clinical (human) or epidemiologic studies: treatment/prevention assessment/controlled clinical trials • choroid: neovascularization