title: Population pharmacokinetic modeling of Thymoglobulin(®) in children receiving allogeneic-hematopoietic cell transplantation: towards improved survival through individualized dosing.
abstract: OBJECTIVE
  To prevent graft-versus-host disease and rejection in hematopoietic cell transplantation (HCT), children receive Thymoglobulin(®), a polyclonal antibody acting mainly by depleting T cells. The therapeutic window is critical as over-exposure may result in delayed immune reconstitution of donor T cells. In this study, we describe the population pharmacokinetics of Thymoglobulin(®) as a first step towards an evidence-based dosing regimen of Thymoglobulin(®) in pediatric HCT.
  
  
  METHODS
  Serum active Thymoglobulin(®) concentrations were measured in all pediatric HCTs performed between 2004 and 2012 in two pediatric HCT centers in The Netherlands. Population pharmacokinetic analysis was performed using NONMEM(®) version 7.2.
  
  
  RESULTS
  A total of 3,113 concentration samples from 280 pediatric HCTs were analyzed, with age ranging from 3 months to 23 years old. The cumulative Thymoglobulin(®) dose was 10 mg/kg in 94 % of the patients given in 4 consecutive days. A model incorporating parallel linear and concentration-dependent clearance of Thymoglobulin(®) was identified. Body weight [for linear clearance (CL) and central volume of distribution] as well as lymphocyte count pre-Thymoglobulin(®) infusion (for CL) were important covariates. As such, the current dosing regimen results in higher exposure in children with a higher bodyweight and/or a lower lymphocyte count pre-Thymoglobulin(®) infusion.
  
  
  CONCLUSIONS
  This model can be used to develop an individual dosing regimen for Thymoglobulin(®), based on both body weight and lymphocyte counts, once the therapeutic window has been determined. This individualized regimen may contribute to a better immune reconstitution and thus outcome of allogeneic HCT.
authors.affiliation: Department of Pediatrics, Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Admiraal
authors.forename: Charlotte
authors.initials: C
authors.lastname: van Kesteren
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Jol-van der Zijde
authors.forename: Maarten J D
authors.initials: MJ
authors.lastname: van Tol
authors.forename: Imke H
authors.initials: IH
authors.lastname: Bartelink
authors.forename: Robbert G M
authors.initials: RG
authors.lastname: Bredius
authors.forename: Jaap Jan
authors.initials: JJ
authors.lastname: Boelens
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000961:Antilymphocyte Serum / Q000008:administration & dosage / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000378:metabolism / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007223:Infant; D018655:Lymphocyte Count; D008297:Male; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; C512542:thymoglobulin