Study objectives: To compare the disposition of cyclosporine after the administration of two oral formulations to children undergoing hematopoietic stem cell transplantation, and to evaluate the relationship between whole blood cyclosporine concentrations during the dosing interval and the area under the whole blood concentration-time curve.
Design: Prospective, descriptive, crossover study.Setting. Hematopoietic stem cell transplantation unit in a tertiary-quaternary university-affiliated pediatric hospital.
Patients: Twenty-four pediatric patients aged 0.5-16.9 years undergoing allogeneic hematopoietic stem cell transplantation.
Intervention: The modified oral formulation of cyclosporine was given on the first day (divided as two doses), and a single identical dose of the original oral formulation was given on the morning of the second day.
Measurements and main results: Blood samples were obtained at 0, 0.5, 1.25, 2, 4, 6, 9, and 12 hours after the morning dose from the lumen of the central venous catheter not previously used for intravenous cyclosporine administration. Cyclosporine concentration-time data were analyzed by using noncompartmental methods. Mean +/- SD maximum concentrations were significantly higher after administration of the modified form than after administration of the original form (594.9 +/- 349.7 vs 483.0 +/- 363.0 microg/L, p=0.003), as was the area under the concentration-time curve from 0-12 hours (AUC0-12; 3432 +/- 1563 vs 3144 +/- 1780 microg/L x hr, p=0.022). For both formulations, cyclosporine concentrations at 4 hours after administration were most strongly correlated with the AUC0-12. Unlike that of the original formulation, the trough cyclosporine concentration of the modified form had the weakest relationship with AUC (Spearman rho coefficient 0.584, p=0.003).
Conclusion: Cyclosporine absorption is lower in children undergoing hematopoietic stem cell transplantation than in children receiving solid organ transplants. Dosage adjustment for the modified formulation based on trough concentration may not be appropriate because its relationship with the AUC was weak. The link between pharmacokinetic parameters and clinical outcomes, such as graft-versus-host disease, must be further studied.