Local tolerance and systemic safety of pegaptanib sodium in the dog and rabbit.
OBJECTIVE
To evaluate the local tolerance, systemic toxicity, and toxicokinetics in dogs and rabbits of pegaptanib sodium, an aptamer that targets vascular endothelial growth factor (VEGF(165)).


METHODS
Dogs received biweekly, bilateral, intravitreous (IVT) injections of pegaptanib sodium for 9 months at doses of 0.3 (n = 10), 1 (n = 10), or 3 mg (n = 14); 14 control dogs received phosphate-buffered saline (PBS). In rabbits, pegaptanib sodium was administered by IVT injection biweekly for 6 months at doses of 0.2 (n = 14), 0.67 (n = 14), or 2 mg (n = 18); 18 rabbits received PBS. The systemic and ocular safety of pegaptanib sodium was assessed. Assessments in both dogs and rabbits included complete ophthalmologic examinations, serum chemistry, hematology, urinalysis, and coagulation assessments, as well as gross and microscopic pathologic examination. In addition, dogs were assessed by electroretinography and electrocardiography. In a cardiovascular safety study, loading intravenous boluses and maintenance infusions of pegaptanib sodium or PBS were administered to dogs (n = 4) in an ascending dose design, with each dose level separated by 2-3 days. The pegaptanib dosing regimens were designed to achieve pegaptanib plasma concentrations of approximately 90, 270, or 900 ng/mL.


RESULTS
There were no pegaptanib sodium-associated clinical, ophthalmologic, pathologic, or cardiovascular abnormalities at doses of pegaptanib that achieved systemic and ocular exposure levels in excess of those associated with the recommended pegaptanib IVT dosing regimen of 0.3 mg per study eye in patients with age-related macular degeneration.


CONCLUSIONS
These studies, together with data from clinical trials, provide strong evidence that inhibition of VEGF(165) by pegaptanib in the eye is a safe therapy for the treatment of ocular neovascular disease.
Foy
Jeffrey W-D
JW
(OSI) Pharmaceuticals, Boulder, CO 80301, USA. jfoy@osip.com
Rittenhouse
Kay
K
Modi
Marlene
M
Patel
Manju
M
D000287:Administration, Topical; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D052157:Aptamers, Nucleotide / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D004285:Dogs; D004562:Electrocardiography; D004596:Electroretinography; D005260:Female; D007267:Injections; D007275:Injections, Intravenous; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D011817:Rabbits; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D014822:Vitreous Body
D020533:Angiogenesis Inhibitors; D052157:Aptamers, Nucleotide; D042461:Vascular Endothelial Growth Factor A; C495058:pegaptanib