Population pharmacokinetic approach for evaluation of treosulfan and its active monoepoxide disposition in plasma and brain on the basis of a rat model

Abstract

Purpose: Efficacy of treosulfan, used in the treatment of marrow disorders, depends on the activity of its monoepoxy-(EBDM) and diepoxy compounds. The study aimed to describe the pharmacokinetics of treosulfan and EBDM in the rat plasma and brain by means of mixed-effects modelling.

Methods: The study had a one-animal-per-sample design and included ninty-six 10-week-old Wistar rats of both sexes. Treosulfan and EBDM concentrations in the brain and plasma were measured by an HPLC-MS/MS method. The population pharmacokinetic model was established in NONMEM software with a first-order estimation method with interaction.

Results: One-compartment pharmacokinetic model best described changes in the concentrations of treosulfan in plasma, and EBDM concentrations in plasma and in the brain. Treosulfan concentrations in the brain followed a two-compartment model. Both treosulfan and EBDM poorly penetrated the blood-brain barrier (ratio of influx and efflux clearances through the blood-brain barrier was 0.120 and 0.317 for treosulfan and EBDM, respectively). Treosulfan plasma clearance was significantly lower in male rats than in females (0.273 L/h/kg vs 0.419 L/h/kg).

Conclusions: The developed population pharmacokinetic model is the first that allows the prediction of treosulfan and EBDM concentrations in rat plasma and brain. These results provide directions for future studies on treosulfan regarding the contribution of transport proteins or the development of a physiological-based model.

Keywords: Alkylating antineoplastic agents; Blood–brain barrier; Epoxy compounds; Population pharmacokinetics.

Fig. 1

Non-enzymatic transformation of treosulfan to the active epoxide compounds

Fig. 2

Study outline and workflow

Fig. 3

Final structural population pharmacokinetic model

Fig. 4

Goodness-of-fit plots for pooled data. Panel a illustrates observed concentrations versus individual predicted concentrations (IPRED), panel b illustrates observed concentrations versus population predicted concentrations (PRED), panel c illustrates conditional-weighted residuals (CWRES) versus time, and panel d illustrates CWRES versus PRED. Panels a and b include a unity line (y = x; thin black line). On each graph a spline line is included (bold black line)

Fig. 5

Visual predictive check (VPC) plots for the analyzed concentrations in each tissue. Circles are measured concentrations, solid lines are median, and dashed lines are 5th and 95th percentiles of measured concentrations, light grey areas are 50% interval of simulated data, dark grey areas are 90% interval of simulated data

Fig. 6

Dependence of systematic treosulfan clearance (CL₁/F) on sex. Box areas represent 25th–75th percentiles with a thick line as a median, whiskers as the minimum and maximum values, and the associated p value