Pegaptanib is a selective vascular endothelial growth factor (VEGF) antagonist. VEGF is a secreted protein that selectively binds and activates its receptors located primarily on the surface of vascular endothelial cells. VEGF induces angiogenesis, and increases vascular permeability and inflammation, all of which are thought to contribute to the progression of the neovascular (wet) form of age-related macular degeneration (AMD), a leading cause of blindness. VEGF has been implicated in blood retinal barrier breakdown and pathological ocular neovascularization.

Pegaptanib is an aptamer, a pegylated modified oligonucleotide, which adopts a three-dimensional conformation that enables it to bind to extracellular VEGF. Under in vitro testing conditions,

pegaptanib binds to the major pathological VEGF isoform, extracellular VEGF₁₆₅, thereby inhibiting VEGF₁₆₅ binding to its VEGF receptors. The inhibition of VEGF₁₆₄, the rodent counterpart of human VEGF₁₆₅, was effective at suppressing pathological neovascularization.

In animals, pegaptanib is slowly absorbed into the systemic circulation from the eye after intravitreous administration. The rate of absorption from the eye is the rate limiting step in the disposition of pegaptanib in animals and is likely to be the rate limiting step in humans.

In humans, a mean maximum plasma concentration of about 80 ng/mL occurs within 1 to 4 days after a 3 mg monocular dose (10 times the recommended dose). The mean area under the plasma concentration-time curve (AUC) is about 25 mg· hr/mL at this dose.

Twenty-four hours after intravitreous administration of a radiolabeled dose of pegaptanib to both eyes of rabbits, radioactivity was mainly distributed in vitreous fluid, retina, and aqueous fluid. After intravitreous and intravenous administrations of radiolabeled pegaptanib to rabbits, the highest concentrations of radioactivity (excluding the eye for the intravitreous dose) were obtained in the kidney. In rabbits, the component nucleotide, 2-fluorouridine is found in plasma and urine after single radiolabeled pegaptanib intravenous and intravitreous doses. In rabbits, pegaptanib is eliminated as parent drug and metabolites primarily in the urine.

Based on preclinical data, pegaptanib is metabolized by endo- and exonucleases.

In humans, after a 3 mg monocular dose (10 times the recommended dose), the average (± standard deviation) apparent plasma half-life of pegaptanib is 10 (± 4) days.

Plasma concentrations do not appear to be affected by age or gender, but have not been studied in patients under the age of 50.

Dose adjustment for patients with renal impairment is not needed when administering the 0.3 mg dose.

Following a single 3 mg dose (10 times the recommended dose), in patients with severe (N=7), moderate (N=18), and mild (N=10) renal impairment, the mean (CV%) pegaptanib AUC values were 37.8 (17%), 26.7 (31%), and 23.6 (21%) mg·hr/mL, respectively. The corresponding C_max values were 96.8 (23%), 81.6 (29.2%), and 66.5 (47%) ng/mL, respectively.

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