1. Shahad Abbas1,2 Alison H Thomson1,2 B) non-malignant patients.
Does a uniformly applied initial IV ciclosporin A dose achieve target trough concentrations in children with malignant and non-malignant disease following allogenic hematopoietic stem cell transplantation?
Shahad Abbas1,2 Alison H Thomson1,2
1NHS Greater Glasgow and Clyde, Glasgow, 2University of Strathclyde, Glasgow
Introduction
Ciclosporin A (CsA) is the most widely used immunosuppressive agent for the prevention of acute graft-versus-host disease (aGVHD) in patients undergoing allogenic hematopoietic stem cell transplantation (HSCT).1
Currently a fixed dose of 3 mg/kg/day is given to all paediatric patients of varying age, weight and disease type.
Target trough concentrations is µg/L for malignant disease and µg/L for non-malignant disease.1
It is not clear whether the current fixed CsA dose achieves these target trough concentrations in all patients.
Methods
A retrospective analysis of the data from the paediatric transplant database of patients aged 1 month to 18 years who underwent allogenic HSCT and received IV CsA as an immunosuppressant at the Royal Hospital for Children (RHC) Glasgow between March 2011 and May 2017 was performed.
Patients were divided into two groups: those with an underlying malignant disease and those with non-malignant disease.
The following data were extracted from drug monitoring forms: age; weight, height, CsA doses, CsA trough concentrations and times.
The final daily dose required to reach target trough concentrations in varying age, weight and disease groups was studied.
The ratio between trough and dose for all patients was averaged to determine the relationship between these two variables and the resulting trough concentrations for different dosing regimens was evaluated.
Aim
To determine if the current fixed dose of 3 mg/kg/day IV CsA dose achieves target trough concentrations in paediatric patients with varying age and weight, and between malignant and non-malignant disease.
Results
Data was collected from 53 patients, in which the initial 3 mg/kg/day CsA dose was increased in 22 malignant patients (73%) and 23 non-malignant patients (100%)
The median final dose to reach target trough concentration was 3.6 mg/kg/day in malignant patients and 5.2 mg/kg/day in non-malignant patients.
The time to achieve target trough concentrations was longer in non-malignant patients compared to malignant patients (13 ± 5 days vs 6 ± 4 days, p <0.0001).
All patients required a dose increase but those who were younger and those with lower weights required a greater increase in dose (Figure 2).
Figure 2: Scatterplot of final CsA dose that achieved target trough concentration for age and weight. A and B represent malignant patients, C and D represent non-malignant patients.
Figure 1: Scatterplot of CsA doses and resulting CsA trough concentration for individual patients A) malignant patients
B) non-malignant patients. A C A B D B
Table 1: Example of number (percentage) of patients who would achieve different concentration ranges with an alternate dosage regimen.
Summary and Conclusions
Starting dose of 3 mg/kg/day is too low to achieve target trough concentrations in malignant and non-malignant disease (Figure 1A & 1B) in children with varying age and weight.
All patients required a dose increase but those with non-malignant disease, those who are younger and with lower weight required a greater increase in dose.
When considering potential alternate dosage regimens either a cut-off at age 6 years (Table 1) or weight 20 kg would be appropriate.
Reference
Barkholt L. Importance of CsA drug monitoring in SCT recipients to minimize GVHD and maximize graft vs. leukemia. Pediatric Transplantation. 2009;13(4):400-3.
Acknowledgements
NES Scotland for funding, haematology pharmacists at RHC Glasgow for advice on study concept/design and Gail Smith, HSCT co-ordinator at RHC Glasgow for assistance with data access.