title: Monitoring ocular drug therapy by analysis of aqueous samples.
abstract: OBJECTIVE
  To assess the value of sampling aqueous humor for measurement of potential molecular targets and for pharmacokinetic analysis.
  
  
  METHODS
  Substudy within the context of clinical trials.
  
  
  METHODS
  Forty patients with macular edema caused by central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO), 11 patients with diabetic macular edema (DME), and 8 patients with neovascular age-related macular degeneration (NVAMD).
  
  
  METHODS
  Assays for potential molecular targets were performed on aqueous samples from patients participating in drug studies (CRVO, BRVO, and DME) or patients receiving standard care (NVAMD). Ranibizumab levels were measured in patients with CRVO or BRVO after the first and second injections of ranibizumab.
  
  
  METHODS
  Aqueous levels of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, and ranibizumab.
  
  
  RESULTS
  Aqueous levels of VEGF were significantly higher in patients with DME than in patients with CRVO, which were significantly higher than those in patients with BRVO. Patients with NVAMD had aqueous VEGF levels in an intermediate range, significantly higher than those in patients with BRVO. One month after the second injection of ranibizumab, 27 of 39 patients with vein occlusions had no residual edema; mean aqueous levels of IL-6, IL-1beta, and TNF-alpha were not greater in patients with residual edema; this provides a blueprint for definitive studies with larger cohorts. There was no significant difference in aqueous ranibizumab levels 1 month after the first injection of 0.5 mg versus injection of 0.3 mg, but 1 month after the second injection ranibizumab levels were significantly higher in eyes injected with 0.5 mg. There were substantial differences in levels among patients, but levels in the same patient at months 1 and 2 were highly correlated. No significant difference in aqueous ranibizumab levels was detected between phakic and pseudophakic patients who received the same dose.
  
  
  CONCLUSIONS
  These data suggest that aqueous samples are useful for investigating potential involvement of molecular targets in various disease processes and for pharmacokinetic or pharmacodynamic studies.
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. pcampo@jhmi.edu
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
authors.forename: David F
authors.initials: DF
authors.lastname: Choy
authors.forename: Diana V
authors.initials: DV
authors.lastname: Do
authors.forename: Gulnar
authors.initials: G
authors.lastname: Hafiz
authors.forename: Syed Mahmood
authors.initials: SM
authors.lastname: Shah
authors.forename: Quan D
authors.initials: QD
authors.lastname: Nguyen
authors.forename: Roman
authors.initials: R
authors.lastname: Rubio
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Arron
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D001082:Aqueous Humor / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D002986:Clinical Trials as Topic; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism; D016903:Drug Monitoring; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007267:Injections; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008268:Macular Degeneration / Q000188:drug therapy* / Q000378:metabolism; D008269:Macular Edema / Q000188:drug therapy* / Q000378:metabolism; D000069579:Ranibizumab; D012170:Retinal Vein Occlusion / Q000188:drug therapy / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014822:Vitreous Body
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab