Intravitreal administration of known phototoxicants in the rabbit fails to produce phototoxicity: implications for phototoxicity testing of intravitreally administered small molecule therapeutics.
BACKGROUND
Intravitreal (ITV) dosing has become a clinically important route of administration for the treatment of uveitis, endophthalmitis, retinal vein occlusion, diabetic macular edema and age-related macular degeneration. Despite this, there are no validated non-clinical models of phototoxicity for ITV products.


OBJECTIVE
The objective of this study was to develop an ITV rabbit model of phototoxicity for use in assessing the photosafety of small molecules therapeutics.


METHODS
Dutch Belted rabbits were intravitreally injected bilaterally with four known phototoxicants: 8-methoxypsoralen, lomefloxacin, doxycycline and stannsoporfrin. Triescence(®), a non-phototoxic triamcinolone acetonide steroid formulation designed for ITV administration, was used as a negative control. One eye was then irradiated with solar-simulated ultraviolet radiation for 30 min, 1 h after dosing, while the other eye was occluded, serving as a non-irradiated control.


RESULTS
Despite the direct administration of known phototoxicants into the vitreous, no evidence of ocular phototoxicity was observed in any dose group. Direct (non-phototoxic) retinal toxicity was observed in the doxycycline dose group only.


CONCLUSIONS
These data suggest that the posterior segment of the rabbit eye is protected against phototoxicity by anatomical and/or physiological mechanisms, and is not a useful model for the assessment of phototoxicity of intravitreally administered molecules.
a Department of Safety Assessment , Genentech , South San Francisco , CA , USA .
Evan A
EA
Thackaberry
a Department of Safety Assessment , Genentech , South San Francisco , CA , USA .
Cynthia
C
Farman
a Department of Safety Assessment , Genentech , South San Francisco , CA , USA .
Vladimir
V
Bantseev
a Department of Safety Assessment , Genentech , South San Francisco , CA , USA .
Chris
C
Schuetz
b Charles River Pathology Associates , Frederick , MD , USA .
Julia F
JF
Baker
c The Animal Eye Center of New Jersey , Little Falls , NJ , USA , and.
Michael H
MH
Brown
d Charles River Laboratories , Horsham , PA , USA.
Douglas B
DB
Learn
D000818:Animals; D004318:Doxycycline / Q000633:toxicity; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D024841:Fluoroquinolones / Q000633:toxicity; D058449:Intravitreal Injections; D008297:Male; D008665:Metalloporphyrins / Q000633:toxicity; D008730:Methoxsalen / Q000633:toxicity; D011817:Rabbits; D054852:Small Molecule Libraries / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods*; D014822:Vitreous Body / Q000187:drug effects*
D024841:Fluoroquinolones; D008665:Metalloporphyrins; D054852:Small Molecule Libraries; C055421:tin mesoporphyrin; C053091:lomefloxacin; D004318:Doxycycline; D008730:Methoxsalen
8-methoxypsoralen; Doxycycline; drug safety; intravitreal administration; lomefloxacin; phototoxicity; safety assessment; stannsoporfrin