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

• Published in: British journal of clinical pharmacology 2019-09, Vol.85 (9), p.2033-2044
• Main Authors: Stoep, M. Y. E. C., Zwaveling, J., Bertaina, A., Locatelli, F., Guchelaar, H. J., Lankester, A. C., Moes, D. J. A. R.
• Format: Article
• Language: English
• Subjects: Adolescent; Age Factors; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Agents, Alkylating - adverse effects; Antineoplastic Agents, Alkylating - pharmacokinetics; Biological Variation, Population; Body Weight - physiology; Busulfan - administration & dosage; Busulfan - adverse effects; Busulfan - analogs & derivatives; Busulfan - pharmacokinetics; Child; Child Development - physiology; Child, Preschool; conditioning regimen; Datasets as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring - methods; Female; haematopoietic stem cell transplantation; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; Infant; Infant, Newborn; Male; Metabolic Clearance Rate - physiology; Models, Biological; Original; paediatric patients; population pharmacokinetics; Predictive Value of Tests; Prospective Studies; Transplantation Conditioning - adverse effects; Transplantation Conditioning - methods; treosulfan
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13995

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.