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Population Pharmacokinetics of Cetuximab in Patients With Squamous Cell Carcinoma of the Head and Neck

Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee (Dr Dirks, Dr Meibohm), and Clinical Pharmacology and Pharmacokinetics, Merck KGaA, Darmstadt, Germany (Dr Nolting, Dr Kovar).

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 µg/mL, central compartment volume V₁ 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 V₁. 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.

Key Words: Cetuximab • population pharmacokinetics • cancer • squamous cell carcinoma • monoclonal antibody • biologic • protein therapeutic

Address for correspondence: Bernd Meibohm, PhD, FCP, Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 874 Union Avenue, Suite 5p, Memphis, TN 38163; e-mail: bmeibohm{at}utmem.edu.

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