title: Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy.
abstract: OBJECTIVE
  Dinutuximab (Unituxin™; ch14.18), a monoclonal antibody against disialoganglioside, improved survival as part of post-consolidation therapy for high-risk neuroblastoma. United Therapeutics Corporation (UTC) assumed ch14.18 production from the National Cancer Institute (NCI); this study evaluates pharmacokinetic comparability, safety, and tolerability of UTC and NCI products.
  
  
  METHODS
  In this randomized, two-sequence crossover study, 28 patients aged ≤8 years with high-risk neuroblastoma received equivalent ch14.18-UTC or ch14.18-NCI doses. Despite comparable protein content, nominal doses differed: 17.5 mg/m(2)/day (ch14.18-UTC) and 25 mg/m(2)/day (ch14.18-NCI). Patients received one product during therapy cycles 1 and 2, the other during cycles 3-5. Ch14.18 pharmacokinetic profile characterization used population modeling (NONMEM(®) version 7.2). A two-compartment model with first-order distribution and elimination processes described pharmacokinetic data. Estimated product parameters were normalized to UTC nominal dose. For pharmacokinetic comparability, the final model was used to estimate exposure ratios (UTC/NCI) and associated 90 % confidence intervals (CIs) for area under the curve from time zero to infinity (AUCinf) and maximum concentration (C max). All comparisons were based on a standardized single-dose regimen (17.5 mg/m(2) over 10 h).
  
  
  RESULTS
  Final-model pharmacokinetic parameters were similar to previously published ch14.18-NCI parameters and comparable for UTC and NCI products. Products' systemic exposures were comparable, with 90 % CIs around ratios for AUCinf (0.96; 90 % CI 0.88-1.04) and C max (1.04; 90 % CI 0.98-1.11) within standard bioequivalence bounds (90 % CI 0.80-1.25). Products' adverse events were similar and consistent with those previously reported.
  
  
  CONCLUSIONS
  Equivalent actual ch14.18-UTC and ch14.18-NCI doses produced comparable exposures, with no notable safety or tolerability differences.
authors.affiliation: Children's Hospital Los Angeles, University of Southern California, 4650 Sunset Blvd, Los Angeles, CA, 90027, USA. amarachelian@chla.usc.edu.
authors.forename: Araz
authors.initials: A
authors.lastname: Marachelian
authors.affiliation: Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA, 19104, USA.
authors.forename: Ami
authors.initials: A
authors.lastname: Desai
authors.affiliation: Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA, 19104, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Balis
authors.affiliation: Vanderbilt University School of Medicine, 2200 Pierce Ave 397 PRB, Nashville, TN, 37232-6310, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Katzenstein
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University School of Medicine, 1405 Clifton Rd NE, Atlanta, GA, 30322, USA.
authors.forename: Muna
authors.initials: M
authors.lastname: Qayed
authors.affiliation: Duke University, DUMC 102382, Durham, NC, 27710, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Armstrong
authors.affiliation: Arkansas Children's Hospital/University of Arkansas for Medical Sciences, 1 Children's Way; Slot 512-23, Little Rock, AR, 72202, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Neville
authors.affiliation: Department of Pediatrics, The University of Chicago, 900 E 57th Street, KCBD, Rm 5100, Chicago, IL, 60637, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cohn
authors.affiliation: School of Pharmacy, Wingate University, 515 N. Main Street, Wingate, NC, 28174, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Bush
authors.affiliation: Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA, 92010, USA.
authors.forename: Rudy
authors.initials: R
authors.lastname: Gunawan
authors.affiliation: United Therapeutics Corporation, 55 TW Alexander Drive, Research Triangle Park, NC, 27709, USA.
authors.forename: Allison Pecha
authors.initials: AP
authors.lastname: Lim
authors.affiliation: National Cancer Institute, 9609 Medical Center Dr, MSC 9739, Bethesda, MD, 20892-9739, USA.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: United Therapeutics Corporation, 55 TW Alexander Drive, Research Triangle Park, NC, 27709, USA.
authors.forename: L Mary
authors.initials: LM
authors.lastname: Smith
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D005732:Gangliosides / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D005732:Gangliosides; C025447:sialogangliosides; C112746:dinutuximab
keywords: Dinutuximab; Pharmacokinetics; Safety; Tolerability; Unituxin; ch14.18