title: Pharmacokinetics of anti-ganglioside GD2 mAb 14G2a in a phase I trial in pediatric cancer patients.
abstract: A phase I trial of a murine anti-ganglioside (GD2) monoclonal antibody (mAb) 14G2a was conducted in 14 neuroblastoma patients and 1 osteosarcoma patient to assess its safety, toxicity and pharmacokinetics in pediatric patients. The pharmacokinetics of mAb 14G2a were biphasic with a t alpha 1/2 of 2.8 +/- 2.8 h and a t beta 1/2 of 18.3 +/- 11.8 h. In general, t beta 1/2 was dose-dependent with a level of significance of P = 0.036, and it reached a plateau at doses of 250 mg/m2 or more. Overall the peak serum levels were dose-dependent at P < 0.001. However, they demonstrated an abrupt increase between doses of 100 mg/m2 and 250 mg/m2. The latter two suggest a saturable mechanism for mAb elimination. In addition, peak serum concentrations were observed earlier at higher mAb doses, which indicates the achievement of a steady state. The t beta 1/2 of mAb 14G2a in children appears to be shorter than in adults. Furthermore, 2 patients demonstrated a considerable decrease in t beta 1/2 following retreatment with 14G2a. This was paralleled by high human anti-(mouse Ig) antibody levels. This study represents the first comprehensive analysis of murine mAb pharmacokinetics in children and will be useful in the future design of mAb therapy.
authors.affiliation: Charité Children's Hospital, Humboldt University at Berlin, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Uttenreuther-Fischer
authors.forename: C S
authors.initials: CS
authors.lastname: Huang
authors.forename: R A
authors.initials: RA
authors.lastname: Reisfeld
authors.forename: A L
authors.initials: AL
authors.lastname: Yu
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D002648:Child; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D009447:Neuroblastoma / Q000628:therapy*; D012516:Osteosarcoma / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D005732:Gangliosides; C019403:ganglioside, GD2