Rick Admiraal, MD (1,2,3), Charlotte van Kesteren, PharmD PhD (1,2), Maarten JD van Tol, PhD (4), Cornelia M Jol van der Zijde, BSc (4), Robbert GM Bredius, MD PhD (3), Jaap Jan Boelens, MD PhD (1), Catherijne AJ Knibbe, PharmD PhD (2)
(1) Department of Pediatric Immunology, University Medical Centre Utrecht, the Netherlands, (2) Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands, (3) Department of Pediatrics, Leiden University Medical Centre, Leiden, the Netherlands, (4) Pediatric Immunology Laboratory, Leiden University Medical Centre, Leiden, the Netherlands
Objectives: To prevent graft versus host disease (GvHD) and rejection in hematopoietic cell transplantation (HCT), children receive anti-thymocyte globulin (ATG), a polyclonal rabbit-derived antibody, as part of the conditioning regimen to deplete T-cells. Besides T-cells, ATG is known to bind to antigens expressed by other lymphocytes, monocytes and endothelium. The therapeutic window is critical: overdosing leads to slow or absent reconstitution of donor T-cells, increasing the risk of viral infections, whereas underdosing may cause GvHD, both causing significant morbidity and mortality. Previous studies have shown drug concentrations to be highly variable over the entire pediatric population when dosing a fixed amount per kg, with older children reaching higher concentrations. The aim of this study is to develop a new dosing regimen in order to improve outcome in pediatric SCT. To reach this goal, a population PK/PD model will be developed to describe T-cell reconstitution, incidence of GvHD and survival in relation to ATG-concentrations.
Methods: Pharmacokinetic and -dynamic data were available from all pediatric HCT’s performed between 2004-2012 in the Netherlands. 260 patients were included with ages varying 0.1 to 22 years. Patients received a cumulative dose of 10 mg/kg ATG divided in four infusions over 4 consecutive days, starting 4 to 15 days before infusing the graft. A median of 12 samples per patient were available, as well as an extensive amount of data on covariates and pharmacodynamic endpoints, including T-cell concentrations and clinical outcomes such as survival, infections and GvHD. NONMEM VII was used for population PK modeling and to perform a covariate analysis characterizing the influence of e.g. bodyweight and age.
Results: Various models have been tested, including models with non-linear clearance. Preliminary results show pharmacokinetics of ATG can be described adequately using a 2-compartment model in terms of volume of distribution, intercompartimental clearance and first-order clearance. Weight is a significant covariate for clearance, volume of distribution and intercompartimental clearance using a power function. Currently, this model is further extended to describe immune reconstitution.
Conclusions: This far, ATG pharmacokinetics can be well described using a two-compartment model with weight as an important covariate. In future, various pharmacodynamics, such as immune reconstitution, will be incorporated in this model to derived evidence based dosing guidelines.
Reference: PAGE 22 (2013) Abstr 2803 [www.page-meeting.org/?abstract=2803]
Poster: Paediatrics