Determination of Area Under the Whole Blood Concentration versus Time Curve after First Intravenous Cyclosporine Dose in Children Undergoing Hematopoietic Stem Cell Transplant: Limited Sampling Strategies

Abstract

Achievement of target trough cyclosporine whole blood concentrations after hematopoietic stem cell transplant (HSCT) reduces the risk of acute graft versus host disease (aGvHD). In solid organ transplant, prevention of acute graft rejection correlates with achievement of target area under the whole blood concentration versus time curve during the 12-hour dosing interval (AUC-12) after oral administration. This study describes a limited sampling strategy for determination of cyclosporine AUC-12 after administration of the first intravenous (IV) dose in children undergoing HSCT and explores the relationships between individual whole blood concentrations during the dosing interval and the AUC.

Children undergoing HSCT and receiving cyclosporine prophylaxis were eligible to participate. The first cyclosporine dose was given as a 2 hour infusion, and eight cyclosporine concentrations were determined at 2 (end of the infusion), 2.5, 3, 4, 6, 8, 10, and 12 hours after the start of the IV infusion. The relationship between AUC-12 and whole blood cyclosporine concentrations at individual time points after IV administration was assessed by the Spearman rho correlation coefficient. Limited sampling strategies were developed using three to six time points by way of multiple linear regression analysis. The agreement between the AUC-12 calculated using all eight data points and the limited sampling strategies was assessed by intraclass coefficient and Bland-Altman analysis.

Twenty-four children (0.5-16.9 yr) participated. The mean AUC-12 calculated using all eight concentration versus time points was 2793 ± 1165.6 μg/L·hr. Whole blood cyclosporine concentrations obtained within the first 4 hours from the start of the infusion correlated strongly with AUC-12 (Spearman rho coefficient, 0.717-0.868). Limited sampling strategies were developed to estimate AUC-12 with adjusted r² of 0.955 to 0.998, mean bias of 0% to 0.93%, and precision of 1.6% to 8.1%. The actual AUC-12 and predicted AUC-12 values agreed strongly (intraclass coefficient, 0.981-0.999).

Limited sampling strategies using three to six data points have been developed that will estimate cyclosporine AUC-12 after administration of the first IV dose given over 2 hours. Information regarding the possible association between aGvHD and cyclosporine AUC-12 is not available. The limited sampling strategies described here will facilitate the prospective evaluation of the clinical importance of cyclosporine AUC-12 in the prevention of aGvHD.