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Population pharmacokinetics of treosulfan in paediatric patients undergoing hematopoietic stem cell transplantation
Author(s) -
Stoep M. Y. E. C.,
Zwaveling J.,
Bertaina A.,
Locatelli F.,
Guchelaar H. J.,
Lankester A. C.,
Moes D. J. A. R.
Publication year - 2019
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13995
Subject(s) - treosulfan , nonmem , population , medicine , transplantation , dosing , hematopoietic stem cell transplantation , pharmacokinetics , busulfan , environmental health
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/m 2 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.