September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Development of a Refillable Intraocular Implant for Sustained Delivery of Tyrosine Kinase Inhibitors
Author Affiliations & Notes
  • Signe R Erickson
    ForSight Vision4, Menlo Park, California, United States
  • Kathleen C Farinas
    ForSight Vision4, Menlo Park, California, United States
  • Judit Horvath
    ForSight Vision4, Menlo Park, California, United States
  • Jay M Stewart
    University of California San Francisco, San Francisco, California, United States
  • Randy Campbell
    ForSight Vision4, Menlo Park, California, United States
  • Footnotes
    Commercial Relationships   Signe Erickson, ForSight Vision4 (E), ForSight Vision4 (P); Kathleen Farinas, ForSight Vision4 (E), ForSight Vision4 (P); Judit Horvath, ForSight Vision4 (E), ForSight Vision4 (P); Jay Stewart, ForSight Vision4 (C); Randy Campbell, ForSight Vision4 (E), ForSight Vision4 (P)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 1128. doi:
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      Signe R Erickson, Kathleen C Farinas, Judit Horvath, Jay M Stewart, Randy Campbell; Development of a Refillable Intraocular Implant for Sustained Delivery of Tyrosine Kinase Inhibitors. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1128.

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

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Abstract

Purpose : Tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptors represent a rational compound class for the treatment of retinal diseases. The purpose of this work was to develop an effective delivery system to leverage the potential of these molecules for treatment of ocular disease.

Methods : Novel injectable formulations were developed for a series of TKIs and coupled with the Port Delivery System (PDS) Implant. Diffusional drug release from the combined system was characterized in an in vitro release apparatus (in PBS pH 7.4 at 37C) and included stability assessment via RP-HPLC. In vivo drug release kinetics were assessed in minipigs by measuring remaining implant drug content. Ocular drug distribution was analyzed by LC-MS/MS. Drug activity was assessed in a VEGF-induced model of retinal leakage in the rabbit. Finally, safety of the system delivering pazopanib was assessed in minipigs via ophthalmic examination, electroretinography, and histopathology.

Results : Formulations were developed which enabled first order sustained release of several TKIs from the PDS Implant. In vitro release of pazopanib was studied for up to 6 months. Pazopanib release rate tunability and consistency was demonstrated with different formulation and implant combinations, yielding cumulative drug release of 41.5 ± 2.6%, 54.3 ± 2.5%, and 82.6 ± 1.6% respectively (n=6 each) at 3 months. Pazopanib remaining in implants at 3 months was 99.6-99.9% main peak by HPLC. Twenty days following implantation in rabbits, implants releasing pazopanib were effective in inhibiting VEGF-induced retinal leakage at levels comparable to a bevacizumab intravitreal injection control. In contrast, a single 0.23 mg intravitreal injection of the pazopanib formulation alone 4 days prior to the VEGF challenge had no inhibitory effect. Following implantation in the minipig, pazopanib levels in vitreous, retina and choroid were sustained over time, with choroid levels at 50 days representing over 300X the published pazopanib IC50 level. Drug release in vivo was comparable to that in vitro. Available interim 3 month results from a 6 month study in the minipig support safety of the combined system.

Conclusions : The PDS Implant coupled with a novel formulation was successful in overcoming the physiochemical challenges of this class of molecules for ocular delivery.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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