Chemical formula: C₆H₁₄O₈S₂ Molecular mass: 278.29 g/mol PubChem compound: 9882105
Treosulfan is a prodrug of a bifunctional alkylating agent with cytotoxic activity to haematopoietic precursor cells. The activity of treosulfan is due to the spontaneous conversion into a mono-epoxide intermediate and L-diepoxybutan. The epoxides formed alkylate nucleophilic centres of deoxyribonucleic acid (DNA) and are able to induce DNA cross-links which are considered responsible for the stem cell depleting and antineoplastic effects.
Treosulfan has a broad antineoplastic and antileukaemic activity. This was demonstrated against transplanted mouse and rat lymphomas/leukaemias, sarcomas and hepatomas, human tumour xenografts, human tumour biopsies and cell lines.
The immunosuppressive effects of treosulfan are attributed to its toxicity against primitive and committed progenitor cells, T and NK cells, reduction of cellularity of primary and secondary lymphatic organs and a preclusive effect on the ‘cytokine storm’ that precedes the development of Graft-versus-Host-Disease (GvHD) and is involved in the pathogenesis of veno-occlusive disease.
Treosulfan is a prodrug that is spontaneously converted under physiological conditions (pH 7.4; 37°C) into a monoepoxide intermediate and L-diepoxybutane with a half-life of 2.2 hours.
After intravenous administration, peak plasma levels are reached at the end of the infusion time. Maximum plasma levels (mean ± SD) in adult patients after a 2-hour intravenous infusion of 10, 12, or 14 g/m² treosulfan were 306 ± 94 μg/mL, 461 ± 102 μg/mL, and 494 ± 126 μg/mL, respectively.
Treosulfan is rapidly distributed in the body; however, its penetration through the blood-brain-barrier is quite limited. The volume of distribution in adult patients is about 20–30 litres. No dose accumulation with the recommended daily treatment on three consecutive days was observed. Treosulfan does not bind to plasma proteins.
Under physiological conditions (pH 7.4, temperature 37°C), the pharmacologically inactive treosulfan is converted spontaneously (non-enzymatically) into the active monoepoxide intermediate (S,S-EBDM = (2S,3S)-1,2-epoxybutane-3,4-diol-4-methanesulfonate) and finally to L-diepoxibutane (S,S-DEB = (2S,3S)-1,2:3,4-diepoxybutane). At concentrations up to 100 μM, treosulfan has no unequivocal effect on CYP1A2, 2C9, 2C19, 2D6, or 3A4 activities in vitro. Therefore, treosulfan is unlikely to participate in, or contribute to, potential CYP450-mediated interactions in vivo.
Plasma concentrations of treosulfan decline exponentially and are best described by a first order elimination process fitted by a two-compartment model. The terminal half-life (T1/2β) of intravenously administered treosulfan (up to 47 g/m²) is approximately 2 hours. Approximately 25–40% of the treosulfan dose is excreted unchanged with the urine within 24 hours, nearly 90% of which within the first 6 hours after administration.
Regression analysis of the area under the curve (AUC0-∞) versus treosulfan dose indicated a linear correlation.
No pharmacokinetic studies with treosulfan were done in patients with severe renal or hepatic impairment, because such patients are generally excluded from alloHSCT. About 25–40% of treosulfan is excreted in urine; however, an influence of renal function on renal clearance of treosulfan was not observed.
Conventional dose calculation simply based on BSA results in a significantly higher exposure (AUC) of smaller children and infants with low BSA compared to adolescents or adults. Therefore, dosing of treosulfan in paediatric patients has to be adapted to the BSA. Mean apparent terminal half-life of treosulfan was comparable between the different age groups and ranged between 1.3 and 1.6 hours.
Due to its alkylating mechanism of action treosulfan is characterised as a genotoxic compound with carcinogenic potential. Specific reproductive and developmental toxicity studies on treosulfan in animals were not conducted. However, during chronic toxicity tests in rats spermatogenesis and ovarian function were significantly affected. Published literature data report on gonadotoxicity of treosulfan in pre-pubertal and pubertal male and female mice. Published data concerning treatment of mice and rats with L-diepoxibutane (the alkylating transformation product of treosulfan) revealed impairment of fertility, uterine-ovarian and sperm development.
In juvenile rat toxicity studies treosulfan induced slight retardation of physical development and a slightly delayed time-point of vaginal opening in females. A very low penetration of blood-brain-barrier by treosulfan was observed in rats. The treosulfan concentrations in brain tissue were 95%–98% lower than in plasma. However, an approximately 3-fold higher exposure in brain tissue of juvenile rats in comparison to young adults was found.
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