Cetuximab Pharmacokinetics Influences Progression-Free Survival of Metastatic Colorectal Cancer Patients

• Published in: Clinical cancer research 2011-10, Vol.17 (19), p.6329-6337
• Main Authors: AZZOPARDI, Nicolas, LECOMTE, Thierry, PAINTAUD, Gilles, TERNANT, David, BOISDRON-CELLE, Michelle, PILLER, Friedrich, MOREL, Alain, GOUILLEUX-GRUART, Valérie, VIGNAULT-DESVIGNES, Céline, WATIER, Herve, GAMELIN, Erick
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Biological and medical sciences; Cancer; Cetuximab; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil - administration & dosage; Fluorouracil - therapeutic use; Gastroenterology. Liver. Pancreas. Abdomen; Human health and pathology; Humans; Hépatology and Gastroenterology; Life Sciences; Male; Medical sciences; Medication; Middle Aged; Neoplasm Metastasis; Pharmaceutical sciences; Pharmacology. Drug treatments; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-11-1081

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. 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. 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). 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.