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Azzopardi, N., Lecomte, T., Ternant, D., Boisdron-Celle, M., Piller, F., Morel, A., Gouilleux-Gruart, V., Vignault-Desvignes, C., Watier, H., Gamelin, E. and Paintaud, G.

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

Clinical Cancer Research 17 (19) 6329-6337

par Frapart - publié le

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.