Population Pharmacokinetic Modeling of Thymoglobulin in Children Receiving Allogeneic Hematopoietic Cell Transplantation (HCT): Towards Individualized Dosing to Improve Survival

Introduction: To prevent graft versus host disease (GvHD) and rejection in hematopoietic cell transplantation (HCT), children receive anti-thymocyte globulin (ATG), a polyclonal antibody depleting T-cells, as part of the conditioning regimen. The therapeutic window is critical as over-exposure may result in delayed reconstitution of donor T-cells and increased risk of viral infections. Our objective is to describe the population pharmacokinetics (PK) of Thymoglobulin as a first step towards an evidence based dosing regimen of Thymoglobulin for HCT in children.

Methods: PK data were collected for all pediatric HCT's performed between 2004-2012 in two study centers in the Netherlands. Serum active Thymoglobulin concentrations were quantified by flow cytometry investigating the binding to a T-cell line. Population modeling and covariate analysis was performed on active Thymoglobulin concentrations using NONMEM 7.2. The final model was internally validated using advanced methods such as bootstrap resampling and NPDE.

Results: A total of 196 HCT's in 183 patients were analyzed (table 1). A two-compartment model yielded a good description of the data in all age groups (figure 1 and 2), with no evidence for non-linear elimination. The population value (SE) for clearance (Cl) and volume of distribution (Vd) of a median individual of 21 kg was 3.4 (0.2) L/day and 8.4 (0.6) L, respectively, with body weight as a significant covariate. The relationship between bodyweight and both Cl and Vd was best described by a power function with an exponent of 0.47 (0.08) and 0.62 (0.07), respectively. Terminal half-life was 4.9 days^-1. Figure 3 illustrates that the currently used dosing regimen of 10 mg/kg leads to higher exposure in older children compared to younger children.

Number of HCTs (n)	196
Number of patients (n)	183
Age (years)	6.55 (0.1-22.7)
Weight (kg)	21 (3.66-96)
BSA (m2)	0.84 (0.14-2.1)
Starting day ATG (days before transplantation)	5.1 (1-19)
Number of samples per patients (n)	12 (4-36)
Diagnosis (%)
Malignancy	48
Immune deficiency	22
Bone marrow failure	8
Metabolic disease	13
Benign hematology	8
Stem cell source (%)
Bone marrow	42
Peripheral blood stem cells	11
CB	43
CB plus haplo or 2nd CB	4
Transplant number (1st,2nd,3rd) (n)	183, 12, 1

Table 1: Patient characteristics, shown as median (range) unless specified otherwise. CB: cordblood

Conclusion: In the validated population PK model for active Thymoglobulin in children, clearance and volume of distribution proved dependent on body weight in a nonlinear manner. Therefore, children with a higher weight are exposed to higher concentrations compared to lower weight children if the currently used dosing regimen of 10 mg/kg bodyweight is used. Once the optimal therapeutic window is determined in pharmacodynamic studies, individualized (weight based) dosing guidelines of Thymoglobulin can be derived leading to better outcome after pediatric HCT.