Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 5, pp 1047–1055

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

  • Ami V. Desai
  • Elizabeth Fox
  • L. Mary Smith
  • Allison Pecha Lim
  • John M. Maris
  • Frank M. Balis
Original Article

DOI: 10.1007/s00280-014-2575-9

Cite this article as:
Desai, A.V., Fox, E., Smith, L.M. et al. Cancer Chemother Pharmacol (2014) 74: 1047. doi:10.1007/s00280-014-2575-9

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.

Keywords

Pharmacokinetics Ch14.18 Dinutuximab Neuroblastoma Child 

Supplementary material

280_2014_2575_MOESM1_ESM.docx (74 kb)
Supplementary material 1 (DOCX 73 kb)
280_2014_2575_MOESM2_ESM.docx (69 kb)
Supplementary material 2 (DOCX 69 kb)
280_2014_2575_MOESM3_ESM.docx (165 kb)
Supplemental Fig. 1 Observational pain score sheet given to parents of subjects to complete prior to, 2 h after the start of each infusion, and at the end of each infusion of ch14.18. A final pain score sheet was completed the morning after the fourth ch14.18 infusion(DOCX 164 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Ami V. Desai
    • 1
  • Elizabeth Fox
    • 1
  • L. Mary Smith
    • 2
  • Allison Pecha Lim
    • 2
  • John M. Maris
    • 1
  • Frank M. Balis
    • 1
  1. 1.Division of OncologyThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  2. 2.United Therapeutics CorporationResearch Triangle ParkUSA