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/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.

Evaluation of treosulfan cumulative exposure in paediatric patients through population pharmacokinetics and dosing simulations

“…The CL value was described using an allometric scaling function using body weight centred at 70 kg and a PMA‐based maturation covariate. The population mean estimate for CL of 16.4 L/h/70 kg was comparable to previously published values from Chiesa et al (17.31 L/h/70 kg), 23 Danielak et al (14.7 L/h/70 kg) 27 and van der Stoep et al (18.8 L/h/70 kg) 43 . The population mean estimate for V in this study was 41.7 L/70 kg, which is comparable to the previously mentioned literature (Chiesa et al, 45.44 L/70 kg; van der Stoep et al, 35.93 L/70 kg; Danielak et al, 35.93 L/70 kg).…”

“…A Hill coefficient value of 2.21 as part of the equation for maturation function was estimated and is close to the estimate of 2.12 obtained by Chiesa et al 23 and above the estimate of 1.2 reported by van der Stoep et al, 43 which may be a reflection of the differences in the patient populations studied. This study investigated patients of median age of 3.5 and sample size of 53, which is fewer than other recently published models.…”

“…A one-compartment PK model for treosulfan was utilised over a two-compartment PK model despite other published models utilising the latter. 23,26,27,43 The one-compartment PK model achieved comparably similar or reduced parameter variability and lower RSE values for the CL and V estimates. Model evaluation results further showed that the PK estimates of CL and V were well parameterised, with tighter bootstrapping intervals for CL (14.9-18.1 L/h) and V (38.8-45.1 L) and low IIV estimates for both parameters (28.7% and 26.0%, respectively) compared with current literature.…”

“…The study cohort is reflective of a unique real‐world population, for whom the data have been used to explore different dosing regimens through use of simulation. A one‐compartment PK model for treosulfan was utilised over a two‐compartment PK model despite other published models utilising the latter 23,26,27,43 . The one‐compartment PK model achieved comparably similar or reduced parameter variability and lower RSE values for the CL and V estimates.…”

Total Body Irradiation Forever? Optimising Chemotherapeutic Options for Irradiation-Free Conditioning for Paediatric Acute Lymphoblastic Leukaemia

“…We may find that it is in these younger (and so smaller) patients where Treosulfan TDM has a role. In order to identify and quantify sources of variability in drug concentration and to predict concentrations in individual patients, PK models have been developed (152)(153)(154). Clearly, the currently available data are not sufficient to inform a practise guideline for TDM of Treosulfan in paediatric ALL-the relationship of Treosulfan exposure to leukaemia-free survival has not been described.…”