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

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• 作者：Ami V. Desai (1)
  Elizabeth Fox (1)
  L. Mary Smith (2)
  Allison Pecha Lim (2)
  John M. Maris (1)
  Frank M. Balis (1)
  
• 关键词：Pharmacokinetics ; Ch14.18 ; Dinutuximab ; Neuroblastoma ; Child
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2014
• 出版时间：November 2014
• 年：2014
• 卷：74
• 期：5
• 页码：1047-1055
• 全文大小：294 KB
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  7. Roth MLM, Tarim J, Piperdi S, Sowers R, Geller D, Gill J, Gorlick R (2014) Ganglioside GD2 as a therapeutic target for antibody-mediated therapy in patients with osteosarcoma. Cancer 120(4):548-54 CrossRef
  8. Svennerholm L, Bostrom K, Fredman P, Jungbjer B, Lekman A, Mansson JE, Rynmark BM (1994) Gangliosides and allied glycosphingolipids in human peripheral nerve and spinal cord. Biochim Biophys Acta 1214(2):115-23 CrossRef
  9. Zeng Y, Fest S, Kunert R, Katinger H, Pistoia V, Michon J, Lewis G, Ladenstein R, Lode HN (2005) Anti-neuroblastoma effect of ch14.18 antibody produced in CHO cells is mediated by NK-cells in mice. Mol Immunol 42(11):1311-319. doi:10.1016/j.molimm.2004.12.018 molimm.2004.12.018" target="_blank" title="It opens in new window">CrossRef
  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):1324-334. doi:10.1056/NEJMoa0911123 CrossRef
  11. Saleh MN, Khazaeli MB, Wheeler RH, Allen L, Tilden AB, Grizzle W, Reisfeld RA, Yu AL, Gillies SD, LoBuglio AF (1992) Phase I trial of the chimeric anti-GD2 monoclonal antibody ch14.18 in patients with malignant melanoma. Hum Antibodies Hybridomas 3(1):19-4
  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):85-1. doi:10.1200/JCO.2006.10.3564 CrossRef
  13. Handgretinger R, Anderson K, Lang P, Dopfer R, Klingebiel T, Schrappe M, Reuland P, Gillies SD, Reisfeld RA, Neithammer D (1995) A phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14.18 in patients with neuroblastoma. Eur J Cancer 31A(2):261-67 CrossRef
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• 作者单位：Ami V. Desai (1)
  Elizabeth Fox (1)
  L. Mary Smith (2)
  Allison Pecha Lim (2)
  John M. Maris (1)
  Frank M. Balis (1)
  
  1. Division of Oncology, The Children’s Hospital of Philadelphia, 3501 Civic Center Boulevard, CTRB 4020, Philadelphia, PA, 19104, USA
  2. United Therapeutics Corporation, 55 TW Alexander Drive, Research Triangle Park, NC, 27709, USA
  
• ISSN：1432-0843

文摘

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.