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Assessing a novel depot delivery strategy for noninvasive administration of VEGF/PDGF RTK inhibitors for ocular neovascular disease.

Abstract：

PURPOSE:Two noninvasive delivery strategies for VEGF/PDGF receptor tyrosine kinase inhibitors (RTKI) were explored that exploited uveal retention as a means for establishing an ocular drug depot: a single oral "loading" dose and topical administration. METHODS:Melanin binding was confirmed by centrifugation and mass spectrometry. Ocular retention was examined in pigmented and albino rats. Ocular release kinetics were measured 3 to 28 days postdosing in pigmented rats. Microautoradiography was used to demonstrate retention of RTKI in the uveal tract. A uveal drug depot of pazopanib was created by a single oral dose prior to induction of laser choroidal neovascularization (CNV). Choroid/retinal pigmented epithelium (RPE) retention of a related RTKI with enhanced topical bioavailability, GW771806, was confirmed by bioanalytics, and its ability to regress CNV compared with pazopanib. RESULTS:Pazopanib and GW771806 directly bound melanin and were retained within the uveal tract of pigmented rats for weeks following a single oral dose. Pazopanib was undetectable systemically following a single oral administration prior to CNV induction, and reduced CNV as well as twice daily dosing. Topical ocular delivery of GW771806 at 5 mg/mL led to high choroidal/RPE exposure and significantly regressed CNV lesions; 2 mg/mL prevented lesion progression. CONCLUSIONS:Uveal retention of drugs such as pazopanib can be used to create a sustained-release depot. Topical GW771806 regressed CNV. These data indicate that topical or infrequent oral loading dose treatment with VEGF/PDGF RTKI retained in the choroid/RPE might allow noninvasive treatments for ocular neovascular disease.

journal_name

Invest Ophthalmol Vis Sci

journal_title

Investigative ophthalmology & visual science

authors

Robbie SJ,Lundh von Leithner P,Ju M,Lange CA,King AG,Adamson P,Lee D,Sychterz C,Coffey P,Ng YS,Bainbridge JW,Shima DT

doi

10.1167/iovs.12-10169

subject

Has Abstract

pub_date

2013-02-27 00:00:00

pages

1490-500

issue

eissn

0146-0404

issn

1552-5783

pii

iovs.12-10169

journal_volume

pub_type

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Assessing a novel depot delivery strategy for noninvasive administration of VEGF/PDGF RTK inhibitors for ocular neovascular disease.