Population pharmacokinetic modeling of Thymoglobulin(®) in children receiving allogeneic-hematopoietic cell transplantation: towards improved survival through individualized dosing.

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.

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.

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.

• Authors: Rick Admiraal, Charlotte van Kesteren, Cornelia M Jol-van der Zijde, Maarten J D van Tol, Imke H Bartelink, Robbert G M Bredius, Jaap Jan Boelens, Catherijne A J Knibbe
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 54 Issue 4 Pg. 435-46 (Apr 2015) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 25466602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antilymphocyte Serum
• Immunosuppressive Agents
• thymoglobulin

Topics

• Adolescent
• Adult
• Algorithms
• Antilymphocyte Serum (administration & dosage, pharmacology)
• Child
• Child, Preschool
• Drug Administration Schedule
• Female
• Graft vs Host Disease (blood, metabolism, prevention & control)
• Hematopoietic Stem Cell Transplantation (methods)
• Humans
• Immunosuppressive Agents (administration & dosage, pharmacology)
• Infant
• Lymphocyte Count
• Male
• Treatment Outcome
• Young Adult