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Population Pharmacokinetics of Treosulfan in Paediatric Patients Undergoing Hematopoietic Stem Cell Transplantation

Population Pharmacokinetics of Treosulfan in Paediatric Patients Undergoing Hematopoietic Stem Cell Transplantation

M Y E C van der Stoep, J Zwaveling, A Bertaina, F Locatelli, H J Guchelaar, A C Lankester, D J A R Moes

Br J Clin Pharmacol. 2019 Sep;85(9):2033-2044.

PMID: 31144349

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP299752	Treosulfan		299-75-2	Price

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