title: Pegaptanib 1-year systemic safety results from a safety-pharmacokinetic trial in patients with neovascular age-related macular degeneration.
abstract: OBJECTIVE
  To characterize the safety, tolerability, and pharmacokinetics of the pegylated anti-vascular endothelial growth factor (VEGF) aptamer pegaptanib sodium in subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD).
  
  
  METHODS
  Prospective 2-cohort study: (1) open-label cohort and (2) randomized, double-masked, uncontrolled multicenter trial.
  
  
  METHODS
  In the combined cohorts, 147 subjects with any angiographic subtype of subfoveal choroidal neovascularization secondary to AMD and best-corrected visual acuities (VAs) in the study eye of 20/40 to 20/320 and in the fellow eye of 20/800 or better received pegaptanib sodium.
  
  
  METHODS
  Subjects were randomized to receive intravitreous pegaptanib sodium (1 mg or 3 mg [3- and 10-fold higher than the 0.3-mg approved dose]) every 6 weeks for 54 weeks.
  
  
  METHODS
  Safety assessments included blood chemistries, urinalyses, vital signs, electrocardiograms, serum antipegaptanib antibody assays, adverse events, VAs, and intraocular pressures. After the first, fourth, and eighth injections, serial blood samples were obtained for quantification of pegaptanib plasma concentrations.
  
  
  RESULTS
  No antipegaptanib immunoglobulin G (IgG) or IgM antibodies were detected. Few systemic adverse events were noted. Mild or moderate ocular adverse events related to the injection procedure were reported in most patients. Pegaptanib did not accumulate in plasma after multiple doses; systemic exposures were similar after the first, fourth, and eighth doses. The mean apparent terminal half-life was 10 days. Evaluation of blood pressure (BP) and urine protein, both of which are known to be affected by systemic VEGF inhibition, indicated no evidence of a pegaptanib treatment effect on these parameters. Mean BP at the end of year 1 remained below 140 mmHg (systolic) and 90 mmHg (diastolic), levels considered hypertension by the American College of Cardiology.
  
  
  CONCLUSIONS
  At doses up to 10-fold higher than the 0.3-mg dose approved for the treatment of AMD, pegaptanib sodium was well tolerated, with no detectable clinical evidence of systemic VEGF inhibition (i.e., no clinically meaningful changes in proteinuria or mean BP) and no clinically relevant ocular inflammation. Most ocular adverse events were related to the injection procedure itself and were mild or moderate in severity.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Rajendra S
authors.initials: RS
authors.lastname: Apte
authors.forename: Marlene
authors.initials: M
authors.lastname: Modi
authors.forename: Harvey
authors.initials: H
authors.lastname: Masonson
authors.forename: Manju
authors.initials: M
authors.lastname: Patel
authors.forename: Lloyd
authors.initials: L
authors.lastname: Whitfield
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Adamis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics; D052157:Aptamers, Nucleotide / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D020256:Choroidal Neovascularization / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007267:Injections; D007429:Intraocular Pressure / Q000187:drug effects; D008268:Macular Degeneration / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011507:Proteinuria / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D014822:Vitreous Body
chemical_list: D020533:Angiogenesis Inhibitors; D052157:Aptamers, Nucleotide; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C495058:pegaptanib