Aims: Treosulfan is an alkylating agent increasingly used prior to haematopoietic stem cell transplantation. The aim of this study was to develop a population pharmacokinetic (PK) model of treosulfan in paediatric haematopoietic stem cell transplantation recipients and to explore the effect of potential covariates on treosulfan PK. Also, a limited sampling model (LSM) will be developed to accurately predict treosulfan exposure suitable for a therapeutic drug monitoring setting. Methods: In this multicentre study, 91 patients, receiving a total dose of 30, 36 or 42 g/m2 treosulfan, administered over 3 consecutive days, were enrolled. A population PK model was developed and demographic factors, as well as laboratory parameters, were included as potential covariates. In addition, a LSM was developed using data from 28 patients. Results: A 2-compartment model with first order elimination best described the data. Bodyweight with allometric scaling and maturation function were identified as significant predictors of treosulfan clearance. Treosulfan clearance reaches 90% of adult values at 4 postnatal years. A model-based dosing table is presented to target an exposure of 1650 mg*h/L (population median) for different weight and age groups. Samples taken at 1.5, 4 and 7 hours after start of infusion resulted in the best limited sampling strategy. Conclusions: This study provides a treosulfan population PK model in children and captures the developmental changes in clearance. A 3-point LSM allows for accurate and precise estimation of treosulfan exposure.

Van Der Stoep, M. Y. E. C., Zwaveling, J., Bertaina, A., Locatelli, F., Guchelaar, H. J., Lankester, A. C., Moes, D. J. A. R., Population pharmacokinetics of treosulfan in paediatric patients undergoing hematopoietic stem cell transplantation, <<BRITISH JOURNAL OF CLINICAL PHARMACOLOGY>>, 2019; 85 (9): 2033-2044. [doi:10.1111/bcp.13995] [https://hdl.handle.net/10807/230062]

Population pharmacokinetics of treosulfan in paediatric patients undergoing hematopoietic stem cell transplantation

Locatelli, Franco
Writing – Review & Editing
;
2019

Abstract

Aims: Treosulfan is an alkylating agent increasingly used prior to haematopoietic stem cell transplantation. The aim of this study was to develop a population pharmacokinetic (PK) model of treosulfan in paediatric haematopoietic stem cell transplantation recipients and to explore the effect of potential covariates on treosulfan PK. Also, a limited sampling model (LSM) will be developed to accurately predict treosulfan exposure suitable for a therapeutic drug monitoring setting. Methods: In this multicentre study, 91 patients, receiving a total dose of 30, 36 or 42 g/m2 treosulfan, administered over 3 consecutive days, were enrolled. A population PK model was developed and demographic factors, as well as laboratory parameters, were included as potential covariates. In addition, a LSM was developed using data from 28 patients. Results: A 2-compartment model with first order elimination best described the data. Bodyweight with allometric scaling and maturation function were identified as significant predictors of treosulfan clearance. Treosulfan clearance reaches 90% of adult values at 4 postnatal years. A model-based dosing table is presented to target an exposure of 1650 mg*h/L (population median) for different weight and age groups. Samples taken at 1.5, 4 and 7 hours after start of infusion resulted in the best limited sampling strategy. Conclusions: This study provides a treosulfan population PK model in children and captures the developmental changes in clearance. A 3-point LSM allows for accurate and precise estimation of treosulfan exposure.
2019
Inglese
Van Der Stoep, M. Y. E. C., Zwaveling, J., Bertaina, A., Locatelli, F., Guchelaar, H. J., Lankester, A. C., Moes, D. J. A. R., Population pharmacokinetics of treosulfan in paediatric patients undergoing hematopoietic stem cell transplantation, <<BRITISH JOURNAL OF CLINICAL PHARMACOLOGY>>, 2019; 85 (9): 2033-2044. [doi:10.1111/bcp.13995] [https://hdl.handle.net/10807/230062]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/230062
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