BACKGROUND: A retrospective study was conducted to analyze interindividual variability of cetuximab pharmacokinetics and its influence on survival (progression-free survival and overall survival [OS]) in a cohort of head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty-four patients received cetuximab as an infusion loading dose of 400 mg/m followed by weekly infusions of 250 mg/m. Twenty-one patients had locally advanced HNSCC, and 13 had metastatic/recurrent HNSCC. Cetuximab concentrations were measured by the enzyme-linked immunosorbent assay, and its pharmacokinetics was analyzed by a population approach. Survivals were analyzed with the log-rank test. RESULTS: Cetuximab pharmacokinetics was best described using a 2-compartment model with both first-order and saturable (zero-order) eliminations. Estimated pharmacokinetic parameters (%CV) were central volume of distribution V1 = 3.18 L (6%), peripheral volume of distribution V2 = 5.4 L (42%), elimination clearance CL = 0.57 L/d (31%), distribution clearance Q = 0.64 L/d, and zero-order elimination rate k0 = 6.72 mg/d (29%). Both V1 and V2 increased with the body surface area. Adjunction of chemotherapy reduced CL and increased k0. OS was inversely related with cetuximab global clearance (P = 0.007) and was higher in patients with severe radiation dermatitis (P = 0.005). CONCLUSIONS: Cetuximab pharmacokinetics in patients with HNSCC can be described using a 2-compartment model combining linear and nonlinear mechanisms of elimination. OS is associated with both cetuximab global clearance and severe radiation dermatitis.
BACKGROUND: A retrospective study was conducted to analyze interindividual variability of cetuximab pharmacokinetics and its influence on survival (progression-free survival and overall survival [OS]) in a cohort of head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty-four patients received cetuximab as an infusion loading dose of 400 mg/m followed by weekly infusions of 250 mg/m. Twenty-one patients had locally advanced HNSCC, and 13 had metastatic/recurrent HNSCC. Cetuximab concentrations were measured by the enzyme-linked immunosorbent assay, and its pharmacokinetics was analyzed by a population approach. Survivals were analyzed with the log-rank test. RESULTS:Cetuximab pharmacokinetics was best described using a 2-compartment model with both first-order and saturable (zero-order) eliminations. Estimated pharmacokinetic parameters (%CV) were central volume of distribution V1 = 3.18 L (6%), peripheral volume of distribution V2 = 5.4 L (42%), elimination clearance CL = 0.57 L/d (31%), distribution clearance Q = 0.64 L/d, and zero-order elimination rate k0 = 6.72 mg/d (29%). Both V1 and V2 increased with the body surface area. Adjunction of chemotherapy reduced CL and increased k0. OS was inversely related with cetuximab global clearance (P = 0.007) and was higher in patients with severe radiation dermatitis (P = 0.005). CONCLUSIONS:Cetuximab pharmacokinetics in patients with HNSCC can be described using a 2-compartment model combining linear and nonlinear mechanisms of elimination. OS is associated with both cetuximab global clearance and severe radiation dermatitis.
Authors: Maddalena Centanni; Dirk Jan A R Moes; Iñaki F Trocóniz; Joseph Ciccolini; J G Coen van Hasselt Journal: Clin Pharmacokinet Date: 2019-07 Impact factor: 6.447