Population pharmacokinetics of treosulfan and development of a limited sampling strategy in children prior to hematopoietic stem cell transplantation

Abstract

PurposeThere is an increasing interest in use of treosulfan (TREO), a structural analogue of busulfan, as an agent in conditioning regimens prior to hematopoietic stem cell transplantation (HSCT), both in pediatric and adult populations. The aim of this study was to develop a population pharmacokinetic model and to establish limited sampling strategies (LSSs) enabling accurate estimation of exposure to this drug.MethodsThe study included 15 pediatric patients with malignant and non-malignant diseases, undergoing conditioning regimens prior to HSCT including TREO administered as a 1 h or 2 h infusion at daily doses of 10, 12, or 14 g/m2. A population pharmacokinetic model was developed by means of non-linear mixed-effect modeling approach in Monolix® software. Multivariate regression analysis and Bayesian method were used to develop 2- and 3-point strategies for estimation of exposure to TREO.ResultsPharmacokinetics of TREO was best described with a two-compartmental linear model with proportional residual error. Following sampling schedules allowed accurate estimation of exposure to TREO: 1 h and 6 h or 1 h, 2 h, and 6 h for a TREO dose 12 g/m2 in a 1 h infusion, or at 2 h and 6 h or 2 h, 4 h, and 8 h for a TREO dose of 12 g/m2 and 14 g/m2 in a 2 h infusion.ConclusionsA two-compartmental population pharmacokinetic model of TREO was developed and successfully used to establish 2- and 3-point LSSs for accurate and precise estimation of TREO AUC0→∞.

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

“…The shaded areas represent the 95% confidence interval around each of the prediction percentiles. A, Present study, B, Ten Brink et al, C, Danielak et al, D, Mohanan et al…”

“…Our model accounted for age and size differences over a wide age range in children (1 month–18 years). To evaluate the prediction accuracy in children, we performed prediction‐corrected VPCs with the previously published treosulfan PK models (Figure B, C and D) build on paediatric data . The prediction‐corrected VPCs show that all 3 models show poor predictions and are not able to properly describe the current dataset.…”

“…Danielak et al also studied covariates, but only weight and sex were examined with weight being a significant covariate . Mohanan et al considered more covariates such as age, BW, body surface area, sex, liver size, liver fibrosis and biochemical parameters .…”

“…To date, only a few papers have described the clinical pharmacokinetics (PK) of treosulfan in children, often based on small sample size datasets . Three population PK models in children have been published, including 1 by our own group (see Table S1).…”

“…Three population PK models in children have been published, including 1 by our own group (see Table S1). However, the sample size of 2 of the 3 studies was limited and, besides bodyweight (BW), no significant covariates could be identified to explain interindividual variability in PK . Also, the inclusion of infants (children aged <2 years) was limited; a population particularly of interest because variability and total exposure seems especially high in this subgroup…”