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.

Pharmacocinétique des anticorps monoclonaux

“…L'analyse des concentrations sériques au cours du temps montre une accélération de leur décroissance lorsque celles-ci deviennent proches de la quantité de cibles disponibles : la pente de décroissance log-linéaire des concentrations est alors remplacée par une courbe convexe vers le haut. Ces phénomènes ont été décrits par modélisation compartimentale en ajoutant un phénomène d'élimination saturable (équation de Michaelis-Menten) au modèle bi-compartimental classique [23]. Les Acm pourraient également être internalisés après fixation de leur portion Fc sur un récepteur Fcγ présent à la surface de la cellule.…”

Population Pharmacokinetics of Therapeutic Monoclonal Antibodies: Examples and Estimation Method Performance Differences

“…Other software and methods used in a couple of studies (21,22) included a conditional first-order method implemented in Winnonmix (Pharsight corporation, Mountain View, NC), and the Monte Carlo parametric expectation maximization (MCPEM) method implemented in an augmented version of ADAPT II (Biomedical Simulations Resource, University of Southern California, Los Angeles, CA). (26) Chimeric mouse/human IgG1 CD25 Renal transplant 2C L Basiliximab (27) Chimeric mouse/human IgG1 CD25 Liver transplant 2C L Bevacizumab (28) CDR-grafted mouse/human IgG1 VEGF Various solid tumors and colorectal, 2C L non-small cell lung, and breast cancer Cetuximab (29) Chimeric mouse/ (17) CDR-grafted mouse/human TAG-72 Colorectal cancer 2C L IgG1-CH2 domain deletion Infliximab (36) Chimeric mouse/human IgG1 TNF-α Ankylosing spondylitis 2C L Infliximab (37) Chimeric mouse/human IgG1 TNF-α Ulcerative colitis 2C L Inolimomab (38) †…”

“…However, based on the prescribing information for these two mAbs, no dose adjustments for gender are recommended based on similar efficacy and safety profiles in males and females (99,100). Race was evaluated as a covariate in a number of population PK studies including bevacizumab (28), cetuximab (29), pertuzumab (43), and alemtuzumab (23), but was not found to influence the PK of any of these mAbs. The percentage of non-Caucasian patients was small in many studies, and may have precluded the ability to identify any possible differences between race groups.…”

“…However, albumin and alkaline phosphatase were found to positively influence the clearance of bevacizumab, and both were correlated with tumor burden in this study. Assessments of physical performance and disease severity using scoring systems such as the Karnofsky performance scale, Psoriasis Area and Severity index (PASI), and Bath Ankylosing Spondylitis Disease Activity index, are commonly evaluated as covariates in population PK studies of mAbs used in areas of oncology and immunology (29,36,40,46). The only study to identify one of these scoring systems as a covariate was a population PK analysis of efalizumab, where PASI was found to have a modest effect on CL/F (33).…”

“…In all but one of the studies, concomitant medication was not found to influence the PK of the mAb. Examples of mAbs where concomitant medication was not identified as a covariate in the population PK analysis include cetuximab (29), rituximab (44), trastuzumab (46), and infliximab (36). Concomitant chemotherapy was identified as a covariate in a population PK analysis of bevacizumab (28).…”