title: Pharmacokinetics of the chimeric anti-GD2 antibody, ch14.18, in children with high-risk neuroblastoma.
abstract: OBJECTIVE
  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/m(2) 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 AUC 0-tlast from courses 1 to 3. Clearance (2 L/day m(2)) 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.
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, 3501 Civic Center Boulevard, CTRB 4020, Philadelphia, PA, 19104, USA, desaia@email.chop.edu.
authors.forename: Ami V
authors.initials: AV
authors.lastname: Desai
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.forename: L Mary
authors.initials: LM
authors.lastname: Smith
authors.forename: Allison Pecha
authors.initials: AP
authors.lastname: Lim
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
mesh_terms: D000465:Algorithms; D000911:Antibodies, Monoclonal / Q000097:blood / Q000235:genetics / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D005260:Female; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D007118:Immunoassay / Q000379:methods; D007223:Infant; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009447:Neuroblastoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000493:pharmacokinetics; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D005732:Gangliosides; D011993:Recombinant Fusion Proteins; C019403:ganglioside, GD2; C112746:dinutuximab