Purpose There 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.
Methods The 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.
Results Pharmacokinetics 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.
Conclusions A 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→∞.