title: Population pharmacokinetic analysis of free and bound aflibercept in patients with advanced solid tumors.
abstract: OBJECTIVE
  Aflibercept (Zaltrap®) is a novel antiangiogenic agent that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-dependent tumor growth. We aimed to characterize the population pharmacokinetics (PK) of free and bound aflibercept in patients with solid tumors to examine the influence of covariates on their PK and to evaluate the proposed dosing regimens by simulation.
  
  
  METHODS
  Data from 9 clinical trials with 1,506 cancer patients receiving aflibercept (2-9 mg/kg every 2 or 3 weeks; 1 h IV infusion) as a monotherapy or in combination with various chemotherapies were included. Free and bound aflibercept concentrations were analyzed using a non-linear mixed-effects modeling approach with MONOLIX 4.1.2.
  
  
  RESULTS
  An approximation of a target-mediated drug disposition model with irreversible binding of free aflibercept to VEGF adequately described the PK of free and bound aflibercept. The typical estimated clearances for free (CL(f)) and bound aflibercept (CL(b)) were 0.88 and 0.19 L/day, respectively. The volumes of distribution for free (V(p)) and bound (V(b)) aflibercept were similar (~4 L). CL f and V(p) increased with body weight and were lower in women. Patients with low albumin (ALB) or high alkaline phosphatase (ALK) had faster CL(f) compared to a typical patient. Pancreatic cancer may be associated with changes in binding of aflibercept to VEGF. Simulations of different dosing regimens showed that adequate saturation of circulating VEGF was achieved with a dose of 4 mg/kg every 2 weeks.
  
  
  CONCLUSIONS
  Aflibercept kinetics was most affected by gender, body weight, ALB, ALK and pancreatic cancer. Simulations supported the rationale for the recommended dose of 4 mg/kg every 2 weeks for aflibercept.
authors.affiliation: Disposition, Safety and Animal Research, Sanofi R&D, 1, Avenue Pierre Brossolette, 91380, Chilly-Mazarin, France. hoai-thu.thai@sanofi.com
authors.forename: Hoai-Thu
authors.initials: HT
authors.lastname: Thai
authors.forename: Christine
authors.initials: C
authors.lastname: Veyrat-Follet
authors.forename: France
authors.initials: F
authors.lastname: Mentré
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Comets
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001835:Body Weight; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012727:Sex Characteristics; D042461:Vascular Endothelial Growth Factor A / Q000097:blood* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor