Abstract
PurposeEfficacy 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.MethodsThe 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.ResultsOne-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).ConclusionsThe 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.
Highlights
Treosulfan is a small, polar molecule that gains importance in the treatment of marrow disorders
The results of clinical trials indicate that treosulfan is effective and well-tolerated in patients with acute myeloid leukemia
Leukemia may recur as an extramedullary relapse in sites other than the bone marrow [11]. It may present as granulocytic sarcomas and chloromas and the central nervous system is one of the most common sites [11,12,13]. These results indicate that pharmacokinetics of treosulfan need further investigation, especially in the aspect of penetration into the central nervous system
Summary
Treosulfan is a small, polar molecule (molecular weight = 279.29 g/mol) that gains importance in the treatment of marrow disorders. Treosulfan itself does not exert a pharmacodynamic effect, and its cytotoxic properties result from the activity of its transformers. These molecules with one ((2S,3S)-1,2-epoxybutane-3,4-diol-4-methanesulfonate, EBDM) or two epoxide rings ((2S,3S)-1,2:3,4-diepoxybutane, DEB) are formed in a pH and temperature-dependent reaction (Fig. 1). Treosulfan was registered for the treatment of ovarian cancer, under the name Ovastat®. In 2004 European Medicines Agency allowed the use of treosulfan in conditioning treatment before hematopoietic progenitor cell transplantation (orphan designation EU/3/04/186). The results of clinical trials indicate that treosulfan is effective and well-tolerated in patients with acute myeloid leukemia
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