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Population pharmacokinetic modeling of Thymoglobulin(®) in children receiving allogeneic-hematopoietic cell transplantation: towards improved survival through individualized dosing.
- Source :
-
Clinical pharmacokinetics [Clin Pharmacokinet] 2015 Apr; Vol. 54 (4), pp. 435-46. - Publication Year :
- 2015
-
Abstract
- Background and Objectives: 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.<br />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.<br />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.<br />Conclusion: 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.
- Subjects :
- Adolescent
Adult
Algorithms
Antilymphocyte Serum administration & dosage
Child
Child, Preschool
Drug Administration Schedule
Female
Graft vs Host Disease blood
Graft vs Host Disease metabolism
Graft vs Host Disease prevention & control
Humans
Immunosuppressive Agents administration & dosage
Infant
Lymphocyte Count
Male
Treatment Outcome
Young Adult
Antilymphocyte Serum pharmacology
Hematopoietic Stem Cell Transplantation methods
Immunosuppressive Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1179-1926
- Volume :
- 54
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Clinical pharmacokinetics
- Publication Type :
- Academic Journal
- Accession number :
- 25466602
- Full Text :
- https://doi.org/10.1007/s40262-014-0214-6