title: Population pharmacokinetics of cetuximab in patients with squamous cell carcinoma of the head and neck.
abstract: Cetuximab is a monoclonal antibody directed against the epidermal growth factor receptor and is indicated in the treatment of squamous cell carcinoma of the head and neck. The population pharmacokinetics of cetuximab were characterized by nonlinear mixed effects modeling (NONMEM V) using a total of 912 concentrations from 143 patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck enrolled in 2 phase I/II studies. Cetuximab pharmacokinetics were best described by a 2-compartment model with Michaelis-Menten-type saturable elimination. Population estimates (between-subject variability, percent coefficient of variation) of the pharmacokinetic parameters were V(max) 4.38 mg/h (15.4%), K(m) 74 mug/mL, central compartment volume V(1) 2.83 L (18.6%), peripheral compartment volume 2.43 L (56.4%), and intercompartmental clearance 0.103 L/h (97.2%). Ideal body weight and white blood cell count were identified as predictors of V(max) and total body weight as a predictor of V(1). Clinical dose adjustments beyond the approved body surface area-based dosing of cetuximab may be warranted in patients with extreme deviations of their actual body weight from ideal body weight. Agreement between simulated and measured concentrations monitored for up to 43 weeks of therapy indicates that cetuximab pharmacokinetic parameters remained constant during prolonged therapy.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Nathanael L
authors.initials: NL
authors.lastname: Dirks
authors.forename: Arno
authors.initials: A
authors.lastname: Nolting
authors.forename: Andreas
authors.initials: A
authors.lastname: Kovar
authors.forename: Bernd
authors.initials: B
authors.lastname: Meibohm
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D000068818:Cetuximab; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D004797:Enzyme-Linked Immunosorbent Assay; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D015337:Multicenter Studies as Topic; D009362:Neoplasm Metastasis; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab