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

Br J Clin Pharmacol. 2019 Sep;85(9):2033-2044. doi: 10.1111/bcp.13995. Epub 2019 Jul 1.

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.

Keywords: conditioning regimen; haematopoietic stem cell transplantation; paediatric patients; population pharmacokinetics; treosulfan.

Publication types

  • Comparative Study
  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Datasets as Topic
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Monitoring / methods
  • Female
  • Hematopoietic Stem Cell Transplantation / adverse effects*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Metabolic Clearance Rate / physiology
  • Models, Biological*
  • Predictive Value of Tests
  • Prospective Studies
  • Transplantation Conditioning / adverse effects
  • Transplantation Conditioning / methods*

Substances

  • Antineoplastic Agents, Alkylating
  • treosulfan
  • Busulfan