Intravitreal administration of the anti-TNF monoclonal antibody infliximab in the rabbit.
BACKGROUND
Tumor necrosis factor (TNF) is known to play an important role in various immune-mediated ocular diseases; intravenous administration of the anti-TNF monoclonal antibody infliximab has proved beneficial in such cases. Since intravitreal injection (when available) is a substitute for systemic administration of various drugs targeting the eye, we aimed to evaluate the safety of intravitreal injection of infliximab in the rabbit eye.


METHODS
Seven groups of New Zealand white rabbits (four animals in each group) received a single unilateral intravitreal injection (0.1 ml) of increasing doses of infliximab (namely 1, 2, 5, 8, 10 or 20 mg infliximab [Remicade]) or a sham injection respectively. Slit-lamp biomicroscopy, fundoscopy and electrophysiology recordings, i.e. scotopic, photopic and flicker responses, were performed at baseline and after 1, 5, 10, 15, 30 and 45 days. Infliximab-injected eyes were compared with sham-injected and with uninjected fellow eyes (n = 28). Animals were euthanized on day 45 for histopathological examination of the retinas.


RESULTS
Clinical examination and electrophysiological testing were consistently unremarkable after either sham or 1 mg or 2 mg infliximab injections. In contrast, electrophysiological recordings were significantly reduced in a dose-dependent manner from day 1 through day 45, after 5, 8, 10 and 20 mg infliximab injections. Flicker responses were the most sensitive in detecting the lower toxic dose of 5 mg. Histopathological findings were similar in uninjected and sham-injected eyes, as well as after 1 mg or 2 mg infliximab injections. Consistent with the functional abnormalities, retinal deformities and diffuse edema were observed after injection of 5 mg or higher doses of infliximab.


CONCLUSIONS
Intravitreal infliximab may be safely administered up to a dose of 2 mg in the rabbit eye. Such doses can be used in the design of future clinical trials assessing the effects of infliximab for selected patients with immune-mediated ocular conditions.
Theodossiadis
Panagiotis G
PG
2nd Department of Ophthalmology, Attikon University Hospital, University of Athens, Athens, Greece. patheo@med.uoa.gr
Liarakos
Vasilios S
VS
Sfikakis
Petros P
PP
Charonis
Alexander
A
Agrogiannis
Georgios
G
Kavantzas
Nikolaos
N
Vergados
Ioannis A
IA
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000633:toxicity; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000633:toxicity; D055253:Color Vision / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D005128:Eye Diseases / Q000188:drug therapy; D005425:Flicker Fusion / Q000187:drug effects; D000069285:Infliximab; D007267:Injections; D008297:Male; D023421:Models, Animal; D055254:Night Vision / Q000187:drug effects; D011817:Rabbits; D012160:Retina / Q000166:cytology / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D014822:Vitreous Body
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab