Journal Article

Population Pharmacokinetic Modeling of Thymoglobulin® in Children Receiving Allogeneic-Hematopoietic Cell Transplantation: Towards Improved Survival Through Individualized Dosing

Bartelink, Imke H., Knibbe, Catherijne A. J., Boelens, Jaap Jan, van Kesteren, Charlotte, Jol-van der Zijde, Cornelia M., van Tol, Maarten J. D., Admiraal, Rick, Bredius, Robbert G. M.

2015

Overview

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.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Adolescent / Adult / Algorithms / Antilymphocyte Serum - administration & dosage / Antilymphocyte Serum - pharmacology / Child / Child, Preschool / Drug Administration Schedule / Female / Graft vs Host Disease - blood / Graft vs Host Disease - metabolism / Graft vs Host Disease - prevention & control / Hematopoietic Stem Cell Transplantation - methods / Humans / Immunosuppressive Agents - administration & dosage / Immunosuppressive Agents - pharmacology / Infant / Internal Medicine / Lymphocyte Count / Male / Medicine / Medicine & Public Health / Original Research Article / Pharmacology/Toxicology / Pharmacotherapy / Treatment Outcome / Young Adult