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

Abstract

To investigate the pharmacokinetics (PK) of intravenous treosulfan in paediatric patients undergoing haematopoietic stem cell transplantation (HSCT) for a broad range of diseases and to explore the impact of different dosing regimens on treosulfan exposure (area under the concentration-time curve, AUC0→∞ ) through dosing simulations. A prospective multicentre PK study was conducted using treosulfan concentration data (n = 423) collected from 53 children (median age 3.5, range 0.2-17.0years) receiving three daily age-guided doses (10-14 g/m2 ). Population PK modelling was performed using NONMEM software, utilising a stepwise forward selection backward elimination method and likelihood-ratio test for screening covariates to describe PK variability. Monte Carlo simulation was used to generate patient PK data for 10 000 virtual paediatric patients and cumulative AUC0→∞ values were evaluated using age, body surface area (BSA) and model-based dosing regimens, targeting 4800 mg*h/L. Treosulfan concentration data were described using a one-compartment PK model with first-order elimination. Population mean (95% CI) estimates for clearance (CL) and volume of distribution (V) were 16.3 (14.9-18.1) L/h and 41.9 (38.8-45.1) L, respectively. Allometrically scaled body weight was the best covariate descriptor for CL and V, and maturational age further explained variability in CL. Dosing simulations indicated that in young patient groups (<2years), a model-based dosing regimen more accurately achieved the target AUC0→∞ (58.3%) over the age (42.6%) and BSA-based (51.3%) regimens. Treosulfan disposition was described through allometric body weight and maturational age descriptors. Model-informed dosing is recommended for patients under 2years. Treosulfan PK parameters and AUC0→∞ were not influenced by patient disease.