Comparison of algorithms for oral busulphan area under the concentration-time curve limited sampling estimate.

BACKGROUND AND OBJECTIVES: Therapeutic drug monitoring (TDM) of the first dose of busulphan during conditioning prior to allogeneic stem cell transplantation provides the possibility of improving the clinical outcome via dose adjustment of subsequent doses. The plasma area under the concentration-time curve (AUC) for busulphan is generally accepted as the parameter that gives the best exposure estimate; however, the sampling frequency needed for reliable AUC calculation remains controversial. The aim of the present investigation was to develop and evaluate a limited sampling model for oral busulphan. METHODS: We have compared models using three to four samples with standard WinNonlin(®) adaptive compartment modeling based on eight samples as reference. The evaluated study population included both adult and pediatric patients, but the linear model was devised using analysis of only pediatric patient plasma concentrations. The present model was developed using data from 23 patients with a mean age of 38 years (range 13-59 years) and was evaluated in 20 pediatric patients with a mean age of 6 years (range 0.1-13 years) as well as 23 adult patients (mean age 43 years; range 18-67 years). RESULTS: In 23 patients, the mean AUC from a curve fitting model (Purves method) and a single compartment model had an intraclass correlation coefficient (ICC) of 0.947. From a log-log plot of AUC values it was evident that using this estimate of the AUC would affect dose adjustment decisions for very few of the patients. Applying the linear model using three samples resulted in an ICC of 0.932, mostly due to worse performance in the adult population. CONCLUSIONS: The present results support the use of limited sampling in clinical TDM for oral busulphan provided adequate algorithms and sampling times are used. Moreover, they also demonstrate the caution that is needed when transferring a pharmacokinetic model from a pediatric population to an adult population.

Therapeutic drug monitoring is essential for intravenous busulfan therapy in pediatric hematopoietic stem cell recipients.

Busulfan is widely used for myeloablative conditioning in HSCT. Intravenous busulfan has been introduced to reduce interindividual variability in plasma levels especially in pediatric patients. TDM of intravenous busulfan was performed in 34 pediatric HSCT patients with malignant (n = 9) and non-malignant (n = 25) diseases (50% of patients

Myeloablative and immunosuppressive properties of treosulfan in mice.

OBJECTIVE: Treosulfan is a prodrug with a specific clinical activity in ovarian carcinoma and other solid tumors. Due to its myeloablative and immunosuppressive effects, its use in conditioning regimens prior to allogeneic stem cell treatment (SCT) has been proposed. In the present preclinical study, myeloablative as well as immunosuppressive properties of treosulfan were compared with those of busulfan and cyclophosphamide. METHODS: Three groups of BALB/c mice were treated with treosulfan, cyclophosphamide, or busulfan at sublethal doses that maintained survival without bone marrow support. The control group was left untreated. At different intervals, colony-forming unit granulocyte macrophage assay was performed on marrow cells. Additionally, immunological analyses were performed using spleen cells. RESULTS: We found that treosulfan and busulfan induced a high and persisting degree of myeloablation, as compared with cyclophosphamide. Moreover, treosulfan was more effective in depletion of splenic B and T cells in comparison with busulfan and cyclophosphamide. Furthermore, T cells isolated from the spleens of treosulfan- or busulfan-treated mice were not responsive to allogeneic cells compared with that observed in controls and cyclophosphamide-treated mice. Treatment with treosulfan induced only interleukin-2 production in spleen cells for a short time and had no significant effect on synthesis of tumor necrosis factor-alpha and/or interferon-gamma as compared with that observed in splenic T cells isolated from mice treated with either busulfan or cyclophosphamide. CONCLUSION: Our findings suggest that treosulfan possesses both myeloablative and immunosuppressive properties and may be used as a single agent for conditioning prior to bone marrow transplantation.