title: Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration.
abstract: OBJECTIVE
  To investigate the maximum tolerated dose of ranibizumab administered as a single intravitreal injection.
  
  
  METHODS
  Open-label, 5-center, uncontrolled, prospective, dose-ranging, interventional case series.
  
  
  METHODS
  Twenty-seven patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) with best-corrected Snellen equivalent visual acuity (VA) of 20/100 or worse and considered ineligible for laser photocoagulation or photodynamic therapy.
  
  
  METHODS
  A single intravitreal injection of ranibizumab was to be administered at 1 of 6 escalating doses (50, 150, 300, 500, 1000, and 2000 microg), with escalation to the next dose level occurring only after the safety and tolerability of the lower dose level was established through postinjection day 14. Follow-up examinations were performed on postinjection days 1, 3, 7, 14, 42, and 90. Enrollment was stopped if > or =2 patients experienced dose-limiting toxicity.
  
  
  METHODS
  The primary safety measures were changes from baseline in VA, intraocular pressure (IOP), intraocular inflammation, and production of antiranibizumab antibody. Dose-limiting toxicity was defined by intraocular inflammation, elevated IOP, reduced VA, or hemorrhage within 90 days after injection.
  
  
  RESULTS
  All patients completed this single intravitreal injection study, and 500 microg of ranibizumab was the maximum tolerated dose. At the higher dose of 1000 microg, significant intraocular inflammation was noted. All adverse events were self-limited, and no infectious endophthalmitis occurred. Aqueous or vitreous ocular inflammation occurred in 12 subjects, with complete resolution within 42 days. In 9 of the subjects, the inflammation was graded as trace to 1+ and required no treatment; in 3 of the subjects, the inflammation was graded as 2+ or 3+, and 2 of the 3 were treated with topical 1% prednisolone acetate. No serum antiranibizumab antibodies were detected. All patients had VA similar or improved compared with baseline values.
  
  
  CONCLUSIONS
  The maximum tolerated single dose of ranibizumab in neovascular AMD patients was 500 microg. Single intravitreal injections of ranibizumab up to a dose of 500 microg were safe and well tolerated in this small group of patients.
authors.affiliation: Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, Florida 33136, USA. prosenfeld@med.miami.edu
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenfeld
authors.forename: Steven D
authors.initials: SD
authors.lastname: Schwartz
authors.forename: Mark S
authors.initials: MS
authors.lastname: Blumenkranz
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
authors.forename: Julia A
authors.initials: JA
authors.lastname: Haller
authors.forename: James D
authors.initials: JD
authors.lastname: Reimann
authors.forename: William L
authors.initials: WL
authors.lastname: Greene
authors.forename: Naveed
authors.initials: N
authors.lastname: Shams
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D020256:Choroidal Neovascularization / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology*; D007267:Injections; D008268:Macular Degeneration / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011446:Prospective Studies; D000069579:Ranibizumab; D012449:Safety; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*; D014792:Visual Acuity; D014822:Vitreous Body / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007128:Immunoglobulin Fragments; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab