Pharmacokinetics and concentration-effect relationship of cetuximab in metastatic colorectal cancer
N. Azzopardi, T. Lecomte, D. Ternant, Piller F, M. Ohresser, H. Watier, E. Gamelin, G. Paintaud
CNRS - UMR 6239 (GICC)
Objectives: Cetuximab is a chimeric monoclonal antibody targeted against epidermal growth factor receptor (EGFR). The aim of our study was to identify factors influencing cetuximab pharmacokinetics and progression-free survival (PFS) in metastatic colorectal cancer (mCRC) patients treated by cetuximab combined with irinotecan and 5-fluorouracil.
Methods: One hundred and two mCRC patients were included in a multi-centric, non-comparative, open-label, phase II study. Cetuximab was administered as an infusion loading dose of 400 mg/m² followed by weekly infusions of 250 mg/m². Irinotecan dose was adjusted according to UGT1A1 genotype. Cetuximab concentrations were described using a two-compartment model with both first-order and saturable (Michaelis-Menten) elimination. A population approach was applied using MONOLIX 3.1. PFS was analyzed using a Cox model.
Results: A total of 1320 blood samples were available for analysis. Population values for pharmacokinetic parameters (between-subject variability, percent coefficient of variation) were: central volume of distribution (V1) = 3.05 L (3.8%), elimination clearance (CL) = 0.47 L/day (24%), peripheral volume of distribution (V2) = 4.41 L (6.1%), intercompartimental clearance (Q) = 0.88 L/day (-), maximum rate (Vmax) = 11.4 mg/day (1.3%) and Michaelis constant (Km) = 0.04 mg/L (-). The parameters V1, V2 and Vmax were influenced by body surface area (BSA). PFS was influenced by total dose/AUC at progression time (p < 10-4), irinotecan dose (p = 0.03) and tumour KRAS status (p = 0.01).
Conclusions: The pharmacokinetics of cetuximab was satisfactorily described using a model combining linear and nonlinear elimination rates. Irinotecan dose, KRAS status and cetuximab pharmacokinetics all influence clinical response to cetuximab.