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.

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 microg/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.

Disposition of two oral formulations of cyclosporine in pediatric patients receiving hematopoietic stem cell transplants.

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.

Life-threatening pulmonary hemorrhages post bone marrow transplantation in Hurler syndrome. Report of three cases and review of the literature.

Hurler syndrome (MPS-IH) is an autosomal recessive mucopolysaccharide storage disorder caused by deficiency of lysosomal alpha-L-iduronidase (IDU) enzyme activity. This results in accumulation of heparan sulfate and dermatan sulfate substances. Untreated children develop progressive developmental deterioration and multisystem morbidity with a median survival of 5 years. Allogeneic bone marrow transplantation (BMT) is the only long-lasting treatment that ameliorates or halts the aggressive course of the disease. Pulmonary hemorrhage (PH) is an unusual complication of BMT and has not been previously reported in MPS-IH post-BMT. We report three children with MPS-IH with life-threatening PH around the time of engraftment. All needed intensive-care support and one child developed recurrent PH that required prolonged ventilation.

Allogeneic bone marrow transplantation in children with chronic myelogenous leukemia.

PURPOSE: To determine the outcome of children undergoing allogeneic bone marrow transplantation for chronic myelogenous leukemia (CML) at the authors' institution. PATIENTS AND METHODS: Between 1985 and 1999, 18 allogeneic bone marrow transplantations were performed in 17 patients with CML at the Hospital for Sick Children in Toronto. Median age at diagnosis was 9.5 years (range 3-17). Fourteen patients had disease in the first chronic phase, one had disease in the second chronic phase, and two had disease in the accelerated phase. Preparative regimens varied, with radiation-based protocols used in eight patients. Thirteen donors were related (11 matched, 2 mismatched); four were unrelated (2 matched, 2 mismatched). Patients received T-cell-replete bone marrow a median of 7.5 months (range 2.2-22) from diagnosis. A median of 3.0 x 10(8)/kg nucleated cells was infused (range 1.6-6.7). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate in 13 children. cyclosporine in three, and methotrexate in one. RESULTS: Primary graft failure occurred in one patient. Grade 2 acute GVHD or more developed in 11 of the 17 children (64%; grade 2 in 4, grade 3 in 7). Chronic GVHD occurred in 6 of the 16 patients at risk (37.5%; 5 extensive, 1 localized). No patient experienced overt or cytogenetic relapse. There were two deaths (12%): one from acute GVHD and cytomegalovirus pneumonia and the other from chronic GVHD. Probability of 5-year event-free survival was 87 +/- 9%. CONCLUSIONS: These results strongly support the practice of allotransplantation in children with CML, even in the setting of advanced disease and histoincompatibility. Efforts should be aimed at reducing the transplantation-related death rate.