Pharmacokinetics of cetuximab after administration of escalating single dosing and weekly fixed dosing in patients with solid tumors

Purpose: Previous studies of cetuximab pharmacokinetics did not fully characterize its elimination phase. The purpose of this trial was to evaluate the pharmacokinetics of cetuximab given as a single dose followed by weekly fixed repeated dosing in patients with solid tumors. Experimental Design: Patients were randomly assigned to treatment with a single 2-hour infusion of cetuximab at doses of 50, 100, 250, 400, or 500 mg/m² followed 3 weeks later by weekly 1-hour infusions of cetuximab at a fixed dose of 250 mg/m². Extended pharmacokinetic sampling was collected through 504 hours after the first drug administration. Trough samples were obtained before each fixed weekly dose. Single and multidose pharmacokinetic variables were correlated with clinical outcomes. Results: Forty patients were enrolled. Pharmacokinetic analysis confirmed previous reports of nonlinear pharmacokinetics for cetuximab. Modeling studies predicted a 90% saturation of clearance at a dose of 260 mg/m². Analyses of weekly trough concentrations indicated a slight accumulation of drug concentrations following repeated weekly dosing. Correlative studies indicated a significant association between cetuximab clearance and both body surface area (P = 0.002) and weight (P = 0.002). The occurrence of rash was significantly associated with disease stability (P < 0.002) but not with cetuximab pharmacokinetic variables. Conclusions: Pharmacokinetic results support using body surface area or weight in calculating individual cetuximab doses. A weekly dose of 250 mg/m² is predicted to nearly fully saturate cetuximab clearance and, by inference, epidermal growth factor receptors. The association between rash and disease stability supports further prospective studies of this relationship.