title: A pharmacokinetic binding model for bevacizumab and VEGF165 in colorectal cancer patients.
abstract: OBJECTIVE
  To characterize the population pharmacokinetics of bevacizumab, its binding properties to VEGF165 and the effect of demographic data and VEGF-A polymorphisms on the interplay between bevacizumab serum pharmacokinetics and VEGF165 serum concentrations in patients with colorectal cancer stage IV.
  
  
  METHODS
  Bevacizumab and VEGF165 data were collected from 19 adult patients with metastatic colorectal cancer enrolled in an observational clinical study. Bevacizumab was administered with one of the following combinations: 5-FU/Leucovorin/Irinotecan, 5-FU/Leucovorin/Oxaliplatin, Capecitabine/Irinotecan at doses ranging from 5 to 10 mg/kg every 2 or 3 weeks. Data analysis was performed using nonlinear mixed-effects modeling implemented in NONMEM 7.3.
  
  
  RESULTS
  A target-mediated drug disposition model adequately described bevacizumab concentration changes over time and its binding characteristics to VEGF165. The estimated clearance of bevacizumab was 0.18 L/day, the free VEGF165 levels at baseline were 212 ng/L, and the elimination rate constant of free VEGF165 was 0.401 day(-1). Body weight was allometrically included in all PK parameters.
  
  
  CONCLUSIONS
  The final model adequately described the pre- and post-dose concentrations of total bevacizumab and free VEGF165 in patients with colorectal cancer. Model parameters were consistent with those previously reported for patients with solid tumors. Correlations between the binding affinity of bevacizumab and the VEGF-2578C/A and VEGF-634G/C polymorphisms were noticed.
authors: Department of Pharmacy, University of Patras, Rio-Patras, Greece, eipanoilia@upatras.gr.
authors: Eirini
authors: E
authors: Panoilia
authors: Emilie
authors: E
authors: Schindler
authors: Epaminontas
authors: E
authors: Samantas
authors: Gerasimos
authors: G
authors: Aravantinos
authors: Haralabos P
authors: HP
authors: Kalofonos
authors: Christos
authors: C
authors: Christodoulou
authors: George P
authors: GP
authors: Patrinos
authors: Lena E
authors: LE
authors: Friberg
authors: Gregory
authors: G
authors: Sivolapenko
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D042461:Vascular Endothelial Growth Factor A / Q000097:blood* / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab