June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Ocular metabolism and melanin binding properties of sunitinib, a dual VEGFR/PDGFR inhibitor, that can safely prolong its efficacy for the treatment of wet AMD
Author Affiliations & Notes
  • Ward Peterson
    Graybug Vision, Inc, Redwood City, California, United States
  • Christopher Crean
    Chatham Biopharma Consulting, Pittsboro, North Carolina, United States
  • Rob Lappin
    AIT Bioscience, Indianapolis, Indiana, United States
  • Joshua Kays
    Graybug Vision, Inc, Redwood City, California, United States
  • Yun Yu
    Graybug Vision, Inc, Redwood City, California, United States
  • Ming Yang
    Graybug Vision, Inc, Redwood City, California, United States
  • Jeffrey Cleland
    Graybug Vision, Inc, Redwood City, California, United States
  • Footnotes
    Commercial Relationships   Ward Peterson, Graybug Vision, Inc. (C), Graybug Vision Inc (E); Christopher Crean, Graybug Vision Inc (C); Rob Lappin, None; Joshua Kays, Graybug Vision Inc (E); Yun Yu, Graybug Vision Inc (E); Ming Yang, Graybug Vision Inc (E); Jeffrey Cleland, Graybug Vision Inc (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1974. doi:
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      Ward Peterson, Christopher Crean, Rob Lappin, Joshua Kays, Yun Yu, Ming Yang, Jeffrey Cleland; Ocular metabolism and melanin binding properties of sunitinib, a dual VEGFR/PDGFR inhibitor, that can safely prolong its efficacy for the treatment of wet AMD. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1974.

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

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Abstract

Purpose : A proprietary depot formulation of sunitinib malate (SM)-loaded microparticles (GB-102) is in preclinical development as an intravitreal (IVT) injection product for the treatment of wet AMD. This work aims to characterize the in vivo release of sunitinib (S) from the depot, the biotransformation of S into a second, equally active moiety desethyl-S (D-S), and the sustained/reversible binding of S to melanin that can prolong the duration of active drug levels in retina and RPE-choroid (RC) following a single IVT injection of GB-102.

Methods : GB-102 (containing 1 mg SM) was dosed as an IVT injection (0.05 mL) in pigmented rabbits. Total S and D-S levels in R, RC, vitreous and in the depot itself were quantified by LC/MS/MS in samples taken from 1-7 months post-dose (PD). S binding to artificial melanin was evaluated in vitro to determine the proportion of free vs melanin-bound drug.

Results : By 2 to 3 months PD, 100% of SM in GB-102 is released from the depot. Peak levels of S in retina and RC at 3-month PD are ~104x and ~105x higher, respectively, than its Ki against VEGFR/PDGFR. Terminal elimination rate of S is 2-3 wks (retina) and 3-4 wks (RC), so that levels of S in retina and RC at 6-month PD remain ~10x and ~1000x higher than its Ki. The % ratio of D-S to S levels in retina is <1% (at 1-month PD) and 10-20% (at 6-7 months PD), indicating that D-S levels in retina are sufficient to contribute to pharmacologic activity at later time points. Approximately 0.1% of S exists as free drug in solution containing artificial melanin. Ocular modeling of the clearance of S, its biotransformation to D-S, and calculated levels of free S collectively support pharmacologically active levels in retina and RC for 5 to 6 months following a single GB-102 injection.

Conclusions : While all of the encapsulated SM is released from the GB-102 depot by 2-3 month post-dose in vivo, two properties of sunitinib can prolong its efficacy for an additional 3 months: Ocular biotransformation into a second active metabolite, and high-capacity, reversible binding to melanin in RPE-choroid as a secondary drug reservoir. These results support a potential twice per year dosing regimen of GB-102 for the treatment for wet AMD.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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