alexa Cetuximab pharmacokinetics influences progression-free survival of metastatic colorectal cancer patients.


Journal of Integrative Oncology

Author(s): Azzopardi N, Lecomte T, Ternant D, BoisdronCelle M, Piller F,

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Abstract PURPOSE: 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. EXPERIMENTAL DESIGN: 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. ©2011 AACR This article was published in Clin Cancer Res and referenced in Journal of Integrative Oncology

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