title: Cetuximab pharmacokinetics influences progression-free survival of metastatic colorectal cancer patients.
abstract: OBJECTIVE
  An ancillary phase II study was conducted to study interindividual variability in cetuximab pharmacokinetics and its influence on progression-free survival (PFS) in metastatic colorectal cancer patients cotreated with irinotecan and 5-fluorouracil.
  
  
  METHODS
  Ninety-six patients received cetuximab as an infusion loading dose of 400 mg/m(2) followed by weekly infusions of 250 mg/m(2). Doses of irinotecan and 5-fluorouracil were adjusted individually. Cetuximab concentrations were measured by ELISA. Compartmental pharmacokinetic parameters were estimated by a population approach, and PFS was analyzed using a Cox model.
  
  
  RESULTS
  Cetuximab pharmacokinetics was best described using a two-compartment model with both first-order and saturable (zero-order) elimination. Estimated pharmacokinetic parameters (% standard error) were as follows: central volume of distribution V(1) = 2.96 L (4%), peripheral volume of distribution V(2) = 4.65 L (6%), elimination clearance CL = 0.497 L/d (4%), distribution clearance Q = 0.836 L/d (8%), and zero-order elimination rate k(0) = 8.71 mg/d (10%). Body surface area influenced V(1), V(2), and k(0). Pretreatment serum albumin influenced CL. Risk of disease progression decreased with cetuximab global clearance (cumulative dose/cumulative area under the concentration versus time curve; P = 0.00016). Median PFS of patients with a cetuximab residual concentration on day 14 below median value was 3.3 months as compared with 7.8 months for the other patients (P = 0.004).
  
  
  CONCLUSIONS
  Cetuximab pharmacokinetics in colorectal cancer patients can be described using a model combining linear and nonlinear elimination rates. PFS is influenced by global clearance of cetuximab, a parameter that can be estimated using cetuximab residual concentration on day 14.
authors.affiliation: Université François Rabelais Tours, Tours, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Azzopardi
authors.forename: Thierry
authors.initials: T
authors.lastname: Lecomte
authors.forename: David
authors.initials: D
authors.lastname: Ternant
authors.forename: Michelle
authors.initials: M
authors.lastname: Boisdron-Celle
authors.forename: Friedrich
authors.initials: F
authors.lastname: Piller
authors.forename: Alain
authors.initials: A
authors.lastname: Morel
authors.forename: Valérie
authors.initials: V
authors.lastname: Gouilleux-Gruart
authors.forename: Céline
authors.initials: C
authors.lastname: Vignault-Desvignes
authors.forename: Hervé
authors.initials: H
authors.lastname: Watier
authors.forename: Erick
authors.initials: E
authors.lastname: Gamelin
authors.forename: Gilles
authors.initials: G
authors.lastname: Paintaud
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D005472:Fluorouracil