June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Enhanced Topical Delivery of a Small Molecule Receptor Tyrosine Kinase Inhibitor (RTKi) via Mucosal-Penetrating Particle Technology
Author Affiliations & Notes
  • Lisa Schopf
    R&D, Kala Pharmaceuticals, Waltham, MA
  • Elizabeth Enlow Enlow
    R&D, Kala Pharmaceuticals, Waltham, MA
  • Alexey Popov
    R&D, Kala Pharmaceuticals, Waltham, MA
  • James Bourassa
    R&D, Kala Pharmaceuticals, Waltham, MA
  • Hongming Chen
    R&D, Kala Pharmaceuticals, Waltham, MA
  • Footnotes
    Commercial Relationships Lisa Schopf, Kala Pharmaceuticals (E); Elizabeth Enlow Enlow, Kala Pharmaceuticals (E), Kala Pharmaceuticals (R), Kala Pharmaceuticals (I), Kala Pharmaceuticals (P); Alexey Popov, Kala Pharmaceuticals (E), Kala Pharmaceuticals (P), Kala Pharmaceuticals (I); James Bourassa, Kala Pharmaceuticals (E); Hongming Chen, Kala Pharmaceuticals (E)
  • Footnotes
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Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1087. doi:
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      Lisa Schopf, Elizabeth Enlow Enlow, Alexey Popov, James Bourassa, Hongming Chen; Enhanced Topical Delivery of a Small Molecule Receptor Tyrosine Kinase Inhibitor (RTKi) via Mucosal-Penetrating Particle Technology. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1087.

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

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Abstract

Purpose: To improve topical ocular drug delivery, we have developed mucosal-penetrating particles (MPP) that rapidly and uniformly coat and penetrate mucosal barriers, including that of the eye, providing superior drug exposure to underlying tissues. The objective of this work was to demonstrate that MPP-based eye drops could enable the topical delivery of a small molecule inhibitor designed to block vascular endothelial growth factor (VEGF) signaling, and serve as a potential therapeutic approach for AMD, eliminating the need for more invasive treatments (ie intravitreal injection).

Methods: Pharmacokinetic (PK) profiling of topically administered axitinib formulated as MPP (axitinib-MPP) was performed in pigmented and non-pigmented rabbits. Ocular irritation was assessed via Draize scoring. PK analysis was performed using WinNonlin software. Pharmacodynamic evaluation was carried out in a rabbit model of VEGF-induced retinal vascular leakage. Formulations were given topically starting 2 days prior to a VEGF injection and continued until termination. Ocular irritation assessments were conducted daily. Fluorescein angiograms were scored blinded to treatment.

Results: Topical axitinib-MPP showed a 5-fold area under the curve enhancement in retinal drug concentration over a non-MPP control in non-pigmented rabbits. A single dose of axitinib-MPP in pigmented rabbits sustained retinal drug levels >40-fold over the cellular IC50 value for KDR, a RTK also known as VEGFR2, out to 24hrs. MPP formulations were well-tolerated, and drug levels peaked earliest for cornea, plasma, and retina and later for iris-ciliary body and choroid. Efficacy of the MPP formulation was demonstrated in a VEGF-induced retinal vascular leakage model. Both vehicle and axitinib-MPP delivered topically every 4hrs over 6 days were well-tolerated. Topically administered axitinib-MPP significantly reduced vascular leakage.

Conclusions: Our results demonstrate that topical delivery of a small molecule RTKi formulated as MPP greatly enhances drug levels in the retina and could be a possibility for the treatment of AMD. These data also validate the significant potential of the MPP technology in creating highly effective topical treatments for a broad range of ocular diseases.

Keywords: 412 age-related macular degeneration • 688 retina • 748 vascular endothelial growth factor  
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