Dataset Information

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

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.

SUBMITTER: van der Stoep MYEC

PROVIDER: S-EPMC6710524 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

van der Stoep M Y E C MYEC Zwaveling J J Bertaina A A Locatelli F F Guchelaar H J HJ Lankester A C AC Moes D J A R DJAR

British journal of clinical pharmacology 20190701 9

<h4>Aims</h4>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.<h4>Methods ...[more]

PMID: 31144349

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Project description:ObjectiveImproved understanding of cyclosporine A (CsA) pharmacokinetics in children undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) is crucial for effective prevention of acute graft-versus-host disease and medication safety. The aim of this study was to establish a population pharmacokinetic (Pop-PK) model that could be used for individualised therapy to paediatric patients undergoing allo-HSCT in China.Design, setting and participantsA retrospective analysis of 251 paediatric HSCT patients who received CsA intravenously in the early post transplantation period at Women and Children's Medical Center in Guangzhou was conducted.Analysis measuresThe model building dataset from 176 children was used to develop and analyse the CsA Pop-Pk model by using the nonlinear mixed effect model method. The basic information was collected by the electronic medical record system. Genotype was analysed by matrix-assisted time-of-flight mass spectrometry. The stability and predictability of the final model were verified internally, and a validation dataset of 75 children was used for external validation. Monte Carlo simulation is used to adjust and optimise the initial dose of CsA in paediatric allo-HSCT patients.ResultsThe typical values for clearance (CL) and volume of distribution ([Formula: see text]) were 14.47 L/hour and 2033.53 L, respectively. The body weight and haematocrit were identified as significant variables for V, while only body weight had an impact on CL. The simulation based on the final model suggests that paediatrics with HSCT required an appropriate intravenous dose of 5 mg/kg/day to reach the therapeutic trough concentration.ConclusionsThe CsA Pop-PK model established in this study can quantitatively describe the factors influencing pharmacokinetic parameters and precisely predict the intrinsic exposure to CsA in children. In addition, our dosage simulation results can provide evidence for the personalised medications TRIAL REGISTRATION NUMBER: ChiCTR2000040561.

Project description:A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with β-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S-EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year overall survival (OS), and thalassemia-free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mg•h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mg•hour/L was significantly associated with better 1-year TFS (97% vs. 81%, P = 0.02) and a trend to better 1-year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre-HCT risk factors also revealed treosulfan exposure <1,660 mg•h/L (hazard ratio (HR) = 3.23; 95% confidence interval (CI) = 1.12-9.34; P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04-13.47; P = 0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.

Dataset Information

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

Publications

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

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