Pharmacokinetics of treosulfan in pediatric patients undergoing hematopoietic stem cell transplantation.
BACKGROUND
High-dose treosulfan is used in conditioning regimens before hematopoietic stem cell transplantation in children. Pharmacokinetic data to optimize treosulfan dosing are scarce in this patient population. The aims of this study were the development and validation of an analytical method for treosulfan in human serum and the development of a pharmacokinetic model for treosulfan in pediatric patients. Furthermore, we aimed to develop a limited sampling strategy to estimate treosulfan systemic exposure with a minimum of inconvenience and risk for the patient.


METHODS
A reversed phase high-performance liquid chromatography method using ultraviolet detection to determine treosulfan in human serum samples was developed and validated according to food and drug administration guidelines. Serum pharmacokinetics after the first treosulfan administration was investigated in 20 children using nonlinear mixed-effect modeling, and a limited sampling strategy was developed and validated.


RESULTS
The assay was validated in a 10-500 mg/L concentration range with a lower limit of quantification of 10 mg/L. Accuracies were within the 90%-110% limit. The coefficients of variation of the within-day imprecision and between-days imprecision were less than 5%. Pharmacokinetics was adequately described with a 1-compartment model. The population estimates for clearance (CL) and volume of distribution were 6.85 L/h and 13.2 L for a typical patient of 20 kg, respectively. Treosulfan exposure could be adequately quantified with 2 samples, at 4 and 7 hours after the start of a 3-hour treosulfan infusion, with a mean deviation of 3% of individual CL and area under the curve based on limited sampling in comparison with the full data set in a total cohort.


CONCLUSIONS
In this study, a bioanalytical method, PK model, and limited sampling model were developed and validated. Furthermore, PK parameters of 20 pediatric patients were analyzed, demonstrating an interpatient variability in area under the curve of 14.5%. This study demonstrates the essential developments in the optimization of treosulfan therapy based on PK data.
*Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center; †LAP&P Consultants; and ‡Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
Marloes H
MH
Ten Brink
Oliver
O
Ackaert
Juliëtte
J
Zwaveling
Robbert G M
RG
Bredius
Frans J
FJ
Smiers
Jan
J
den Hartigh
Arjan C
AC
Lankester
Henk-Jan
HJ
Guchelaar
D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008954:Models, Biological; D014481:United States; D014486:United States Food and Drug Administration
D018906:Antineoplastic Agents, Alkylating; C018404:treosulfan; D002066:Busulfan