Pegaptanib

Pegaptanib is a pegylated modified oligonucleotide that binds with high specificity and affinity to extracellular Vascular Endothelial Growth Factor (VEGF165) inhibiting its activity. VEGF is a secreted protein that induces angiogenesis, vascular permeability and inflammation, all of which are thought to contribute to the progression of the neovascular (wet) form of AMD.

Pharmacodynamic effects

VEGF₁₆₅ is the VEGF isoform preferentially involved in pathological ocular neovascularisation. The selective inhibition in animals with pegaptanib proved as effective at suppressing pathological neovascularisation as pan-VEGF inhibition, however pegaptanib spared the normal vasculature whereas pan-VEGF inhibition did not.

Reductions in the growth of mean total lesion size, choroidal neovascularisation (CNV size), and fluorescein leak size, have been shown in patients with AMD treated with pegaptanib.

Absorption

In animals, pegaptanib is slowly absorbed into the systemic circulation from the eye after intravitreal 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 in humans. In humans, the average ± standard deviation apparent plasma half-life of pegaptanib after a 3 mg (10-times the recommended dose) monocular dose is 10 ± 4 days.

A mean maximum plasma concentration of about 80 ng/ml occurs within 1 to 4 days after a 3 mg monocular dose in humans. The mean area under the plasma concentration-time curve (AUC) is about 25 μg·hr/ml at this dose. Pegaptanib does not accumulate in the plasma when administered intravitreally every 6 weeks. At doses below 0.5 mg/eye, pegaptanib plasma concentrations do not likely exceed 10 ng/ml.

The absolute bioavailability of pegaptanib after intravitreal administration has not been assessed in humans, but is approximately 70-100% in rabbits, dogs and monkeys.

In animals that received doses of pegaptanib up to 0.5 mg/eye to both eyes, plasma concentrations were 0.03% to 0.15% of those in the vitreous humour.

Distribution, biotransformation and elimination

In mice, rats, rabbits, dogs and monkeys, pegaptanib distributes primarily into plasma volume and is not extensively distributed to peripheral tissues after intravenous administration. Twenty-four hours after intravitreous administration of a radiolabeled dose of pegaptanib to both eyes of rabbits, radioactivity was mainly distributed in vitreous humour, retina and aqueous humour. After intravitreal and intravenous administrations of radiolabeled pegaptanib to rabbits, the highest concentrations of radioactivity (excluding the eye for the intravitreal 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 intravitreal doses. Pegaptanib is metabolised by endo and exonucleases. In rabbits, pegaptanib is eliminated as parent drug and metabolites primarily in the urine.

Special populations

Pegaptanib pharmacokinetics is similar in female and male patients and within the age range 50 to 90 years.

Pegaptanib sodium has not been adequately studied in patients with creatinine clearance below 20 ml/min. A decrease in creatinine clearance down to 20 ml/min may be associated with up to a 2.3-fold increase in pegaptanib AUC. No special considerations are needed in patients with creatinine clearance above 20 ml/min who are treated with the recommended dose of pegaptanib sodium 0.3 mg.

Pegaptanib pharmacokinetics have not been studied in patients with hepatic impairment. The systemic exposure is expected to be within a well tolerated range in patients with hepatic impairment, as a 10 fold higher dose (3 mg/eye) was well tolerated.

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. There are no studies on the carcinogenic potential of pegaptanib.

Pegaptanib produced no maternal toxicity and no evidence of teratogenicity or foetal mortality in mice at intravenous doses of 1 to 40 mg/kg/day. Reduced body weight (5%) and minimal delayed ossification in forepaw phalanges were observed, only at exposure levels based on AUC of over 300 fold greater than that expected in humans. These finding are therefore considered to be of limited clinical relevance. In the 40 mg/kg/day group, pegaptanib concentrations in the amniotic fluid were 0.05% of the maternal plasma levels. There are no reproductive toxicity studies in rabbits. No data are available to evaluate male or female mating or fertility indices.