title: Integrating disease progression models, non-clinical pharmacokinetic data and treatment response endpoints to optimize intravitreal dosing regimens.
abstract: OBJECTIVE
  To rapidly identify patients who will ultimately respond to 1 year of therapy, and optimize their inter dose interval.
  
  
  METHODS
  An intravitreal (IVT) ophthalmic dosing paradigm was designed based on clinical efficacy, nonclinical pharmacokinetics (PK), and disease progression modeling. Relevant non-clinical PK models were used to extrapolate IVT drug concentrations to patients.
  
  
  RESULTS
  Modeling predicted that > 80% of patients who would respond to 1 year of IVT treatment with an improvement in best-corrected visual acuity (BCVA) could be identified after the first 2 doses of treatment. These 2 initial doses produced ~ 75% of the maximum improvement in BCVA attainable. Moreover, the models also predicted those patients who responded after 1 year of treatment may tolerate an extension of the inter dose interval to 12 weeks without significant deterioration of BCVA. In contrast, > 70% of responsive patients who did not respond to 1 year of treatment showed inadequate responses after 2 doses.
  
  
  CONCLUSIONS
  These models use data from 2 doses to identify those patients likely to benefit after 1 year of treatment, and thereafter can lengthen their inter dose interval without deleterious effects. This method identifies potential treatment responders early, and lengthens the inter dose interval during long-term administration while allowing non-responders to pursue alternative therapies earlier, thereby minimizing risk to the patient.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Basile
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Johnson
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Klamerus
authors.forename: Duo
authors.initials: D
authors.lastname: Zhou
authors.forename: Marla B
authors.initials: MB
authors.lastname: Sultan
authors.forename: Mike
authors.initials: M
authors.lastname: Amantea
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Nickens
mesh_terms: D052157:Aptamers, Nucleotide / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018450:Disease Progression; D006801:Humans; D058449:Intravitreal Injections; D008954:Models, Biological; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D014792:Visual Acuity / Q000187:drug effects
chemical_list: D052157:Aptamers, Nucleotide; D042461:Vascular Endothelial Growth Factor A; C495058:pegaptanib