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

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

R. Admiraal · C. van Kesteren · I. H. Bartelink · J. J. Boelens Department of Pediatrics, Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands
R. Admiraal · C. van Kesteren · C. A. J. Knibbe (&) Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, PO box 9502, 2300 RA Leiden, The Netherlands e-mail: [email protected]
R. Admiraal · C. M. Jol-van der Zijde · M. J. D. van Tol · R. G. M. Bredius Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
R. Admiraal · C. van Kesteren · J. J. Boelens U-DANCE, Tumor immunology, Laboratory Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
I. H. Bartelink Department of Bioengineering and Therapeutic Sciences, University of San Francisco, San Francisco, CA, USA
C. A. J. Knibbe Department of Clinical Pharmacy, Sint Antonius Hospital, Nieuwegein, The Netherlands

Published online: 3 December 2014

Electronic supplementary material The online version of this article (doi:10.1007/s40262–014–0214–6) contains supplementary material, which is available to authorized users.

Clinical Pharmacokinetics 54(4):p 435-446, April 2015. | DOI: 10.1007/s40262-014-0214-6

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