June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
D-Arginine as a Novel Excipient Resulted in Retinal Degeneration Following Intravitreal Administration to Male New Zealand White Rabbits
Author Affiliations & Notes
  • Roxanne Andaya
    Genentech, Inc., South San Francisco, California, United States
  • Helen Booler
    Genentech, Inc., South San Francisco, California, United States
  • Charly Sioson
    Genentech, Inc., South San Francisco, California, United States
  • Vladimir Bantseev
    Genentech, Inc., South San Francisco, California, United States
  • Footnotes
    Commercial Relationships   Roxanne Andaya, None; Helen Booler, None; Charly Sioson, None; Vladimir Bantseev, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5183. doi:
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    • Get Citation

      Roxanne Andaya, Helen Booler, Charly Sioson, Vladimir Bantseev; D-Arginine as a Novel Excipient Resulted in Retinal Degeneration Following Intravitreal Administration to Male New Zealand White Rabbits
      . Invest. Ophthalmol. Vis. Sci. 2017;58(8):5183.

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

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Abstract

Purpose : High osmolality and high viscosity solutions are common problems in ophthalmology intravitreal (ITV) drug development. With a majority of drug excipients excluded from ITV ophthalmic drugs because of safety concerns unique to the eye, investigation into novel excipients for ITV drug administration is warranted. This study aimed to characterize the tolerability and toxicity of D-arginine as a novel excipient following ITV administration to rabbits.

Methods : Rabbits received a single ITV dose of buffered D-arginine-HCl solution ranging from 3.5 to 8.7 mg/eye (375-816 mOsm/kg). Another set of rabbits were given a single ITV dose of vehicle formulations with matched levels of tonicity. The duration of the in-life phase was 8 days, with gross clinical observations and body weights recorded daily. Intraocular pressure (IOP) measurements, indirect ophthalmoscopic examination and slit lamp biomicroscopic examination were performed. Clinical pathology and macroscopic and microscopic anatomic pathology were performed at interim and terminal necropsies, Day 2 and Day 8, respectively.

Results : ITV administration of D-arginine resulted in retinal toxicity at doses of 3.5 mg/eye and higher. The observed changes noted on Day 2, were irreversible and still progressing at Day 8, indicating that the lesions identified would eventually lead to loss of sight. High tonicity vehicles induced retinal changes at 534 mOsm/kg and above. The majority of retinal changes, including vacuolation of the photoreceptor layer were reversible; however, irreversible changes were identified at tonicities of 534 mOsm and above. Although no toxicity was observed during the in-life ophthalmic examinations, the histopathology revealed that intravitreally administered D-arginine is not tolerated in rabbits.

Conclusions : These data show that D-arginine is not a suitable excipient for ITV drug administration due to the severe retinal toxicity observed following ITV administration in rabbits. Further work is required to determine the mechanism of toxicity.

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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