title: SYSTEMIC PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRAVITREAL AFLIBERCEPT, BEVACIZUMAB, AND RANIBIZUMAB.
abstract: OBJECTIVE
  To evaluate the systemic pharmacokinetics (PKs) of aflibercept, bevacizumab, and ranibizumab in patients with neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO).
  
  
  METHODS
  Prospective, open-label, nonrandomized clinical trial of patients with AMD, DME, or RVO who were antivascular endothelial growth factor (VEGF) naïve or had not received anti-VEGF for ≥4 months. Patients received 3 monthly intravitreal injections of aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab (0.5 mg for AMD/RVO, 0.3 mg for DME). The main outcome measures were serum PKs and plasma free-VEGF concentrations after the first and third injections.
  
  
  RESULTS
  A total of 151 patients were included. In AMD/DME/RVO, systemic exposure to each drug was highest with bevacizumab, then aflibercept, and lowest with ranibizumab. Ranibizumab cleared from the bloodstream more quickly than bevacizumab or aflibercept. Aflibercept treatment resulted in the greatest reductions in plasma free-VEGF relative to baseline levels, whereas ranibizumab treatment resulted in the smallest decreases in plasma free-VEGF.
  
  
  CONCLUSIONS
  The three anti-VEGF treatments examined in this analysis demonstrated notable differences in systemic PKs. Generally, the reduction in plasma free-VEGF levels correlated with elevated levels of circulating anti-VEGF agents, with the reduction in free-VEGF levels greatest with aflibercept and least with ranibizumab.
authors.affiliation: *California Retina Consultants, Santa Barbara, California; and †Genentech, Inc, South San Francisco, California.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Avery
authors.forename: Alessandro A
authors.initials: AA
authors.lastname: Castellarin
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Steinle
authors.forename: Dilsher S
authors.initials: DS
authors.lastname: Dhoot
authors.forename: Dante J
authors.initials: DJ
authors.lastname: Pieramici
authors.forename: Robert
authors.initials: R
authors.lastname: See
authors.forename: Stephen
authors.initials: S
authors.lastname: Couvillion
authors.forename: Maʼan A
authors.initials: MA
authors.lastname: Nasir
authors.forename: Melvin D
authors.initials: MD
authors.lastname: Rabena
authors.forename: Mauricio
authors.initials: M
authors.lastname: Maia
authors.forename: Sherri
authors.initials: S
authors.lastname: Van Everen
authors.forename: Kha
authors.initials: K
authors.lastname: Le
authors.forename: William D
authors.initials: WD
authors.lastname: Hanley
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D000068258:Bevacizumab / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003930:Diabetic Retinopathy / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000069579:Ranibizumab / Q000008:administration & dosage / Q000493:pharmacokinetics*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000097:blood; D057135:Wet Macular Degeneration / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*
chemical_list: D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab