Pharmacokinetics of the chimeric anti-GD2 antibody, ch14.18, in children with high-risk neuroblastoma
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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.
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.
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.
Ch14.18 disposition in children is less variable than previously reported. Clearance is age dependent and more rapid in younger children.
KeywordsPharmacokinetics Ch14.18 Dinutuximab Neuroblastoma Child
- 10.Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM (2010) Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. New Engl J Med 363(14):1324–1334. doi:10.1056/NEJMoa0911123 PubMedPubMedCentralCrossRefGoogle Scholar
- 12.Gilman AL, Ozkaynak MF, Matthay KK, Krailo M, Yu AL, Gan J, Sternberg A, Hank JA, Seeger R, Reaman GH, Sondel PM (2009) Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children’s Oncology Group. J Clin Oncol 27(1):85–91. doi:10.1200/JCO.2006.10.3564 PubMedPubMedCentralCrossRefGoogle Scholar
- 14.Ozkaynak MF, Sondel PM, Krailo MD, Gan J, Javorsky B, Reisfeld RA, Matthay KK, Reaman GH, Seeger RC (2000) Phase I study of chimeric human/murine anti-ganglioside G(D2) monoclonal antibody (ch14.18) with granulocyte-macrophage colony-stimulating factor in children with neuroblastoma immediately after hematopoietic stem-cell transplantation: a Children’s Cancer Group Study. Journal of clinical oncology: official journal of the American Society of. Clin Oncol 18(24):4077–4085Google Scholar
- 16.Murray JL, Kleinerman ES, Jia SF, Rosenblum MG, Eton O, Buzaid A, Legha S, Ross MI, Thompson L, Mujoo K, Rieger PT, Saleh M, Khazaeli MB, Vadhan-Raj S (1996) Phase Ia/Ib trial of anti-GD2 chimeric monoclonal antibody 14.18 (ch14.18) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in metastatic melanoma. J Immunother Emphas Tumor Immunol 19(3):206–217CrossRefGoogle Scholar
- 21.Merkel SIV-LT, Shayevitz JR, Malviya S (1997) The FLACC: a behavioral scale for scoring postoperative pain in young children. Pract Appl Res 23(3):293–297Google Scholar