Pharmacokinetics of the chimeric anti-GD2 antibody, ch14.18, in children with high-risk neuroblastoma

Abstract

Purpose: Ch14.18 improves survival in children with high-risk neuroblastoma but is associated with substantial toxicity. Ch14.18 pharmacokinetics were previously reported to be highly variable and characterized by a higher clearance in children than in adults, and a large volume of distribution. Identifying factors responsible for its variability could lead to alternative dosing strategies that reduce toxicity. Methods: Plasma sampling was performed prior to, during, and for 25 days after four daily 10-h infusions of 25 mg/m2 of ch14.18 administered with sargramostim. Ch14.18 concentrations were quantified with an electrochemiluminescence immunoassay, and pharmacokinetic parameters were derived using non-compartmental methods and from fitting a two-compartment model. Human anti-chimeric antibody (HACA) was measured before each course. Results: Fourteen subjects (median age, 4.3 years) were enrolled; seven had sampling on two courses to assess intra-subject variability. Mean peak ch14.18 plasma concentration was 11 μg/mL, and disappearance was biexponential with half-life of 7 days. Mean trough (day 28) concentration was 0.2 μg/mL. Mean AUC0-∞ was 1,380 μg h/mL and was less variable than previously reported (CV 29 %). Intra-patient variability was also minimal, but one subject who developed HACA had a 41 % decrease in AUC0-tlast from courses 1 to 3. Clearance (2 L/ day m2) was fourfold higher in children than in adults and appeared to be age dependent. Steady state volume of distribution was 0.4 L/kg. Two-compartment model parameters were used to simulate alternative dosing schedules. Conclusions: Ch14.18 disposition in children is less variable than previously reported. Clearance is age dependent and more rapid in younger children.