title: A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects.
abstract: OBJECTIVE
  Aflibercept (VEGF-Trap), a novel anti-angiogenic agent that binds to VEGF, has been investigated for the treatment of cancer. The aim of this study was to develop a mechanism-based pharmacokinetic (PK) model for aflibercept to characterize its binding to VEGF and its PK properties in healthy subjects.
  
  
  METHODS
  Data from two phase I clinical studies with aflibercept administered as a single intravenous infusion were included in the analysis. Free and bound aflibercept concentration-time data were analysed using a nonlinear mixed-effects modelling approach with MONOLIX 3.1.
  
  
  RESULTS
  The best structural model involved two compartments for free aflibercept and one for bound aflibercept, with a Michaelis-Menten type binding of free aflibercept to VEGF from the peripheral compartment. The typical estimated clearances for free and bound aflibercept were 0.88 l day(-1) and 0.14 l day(-1), respectively. The central volume of distribution of free aflibercept was 4.94 l. The maximum binding capacity was 0.99 mg day(-1) and the concentration of aflibercept corresponding to half of maximum binding capacity was 2.91 µg ml(-1). Interindividual variability of model parameters was moderate, ranging from 13.6% (V(max) ) to 49.8% (Q).
  
  
  CONCLUSIONS
  The present PK model for aflibercept adequately characterizes the underlying mechanism of disposition of aflibercept and its nonlinear binding to VEGF.
authors.affiliation: Global Metabolism and Pharmacokinetics Department, Sanofi-aventis, Paris, France. hoai-thu.thai@inserm.fr
authors.forename: Hoai-Thu
authors.initials: HT
authors.lastname: Thai
authors.forename: Christine
authors.initials: C
authors.lastname: Veyrat-Follet
authors.forename: Nicole
authors.initials: N
authors.lastname: Vivier
authors.forename: Catherine
authors.initials: C
authors.lastname: Dubruc
authors.forename: Gerard
authors.initials: G
authors.lastname: Sanderink
authors.forename: France
authors.initials: F
authors.lastname: Mentré
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Comets
mesh_terms: D002986:Clinical Trials as Topic; D006801:Humans; D008297:Male; D008954:Models, Biological; D011485:Protein Binding; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor