Pharmacokinetics of treosulfan and its active monoepoxide in pediatric patients after intravenous infusion of high-dose treosulfan prior to HSCT

Penetration of Treosulfan and its Active Monoepoxide Transformation Product into Central Nervous System of Juvenile and Young Adult Rats

“…However, HSCT patients receive much higher TREO doses than 3.5 g/m 2 , namely 10-14 g/m 2 . Consequently, the plasma drug C max reaches 1-3 mM (Główka et al, 2010(Główka et al, , 2015, which is similar to that observed in our study in the rats' plasma. Additionally, TREO C max found in the rats' brain (about 120 mM in the JR and 60 mM in the YAR) is higher than the concentrations reported to efficiently inhibit a viability of leukemia cells obtained from pediatric patients (Munkelt et al, 2008).…”

“…Comparison of brain exposure to TREO and busulfan in HSCT patients should not be based on the rat rough brain/plasma AUC ratios, because TREO is administered in much higher doses than busulfan (12-14 g/m 2 versus 0.8 mg/kg) and achieves much higher plasma concentrations (Hoy and Lyseng-Williamson, 2007;Główka et al, 2010Główka et al, , 2015. As shown in Table 4, despite TREO and S,S-EBDM penetrating across the BBB weaker than busulfan, in the brain of patients conditioned before HSCT, TREO is supposed to achieve much higher AUC compared with busulfan, whereas S,S-EBDM is expected to have a similar AUC.…”

Activation of Prodrug Treosulfan at pH 7.4 and 37°C Accompanied by Hydrolysis of Its Active Epoxides: Kinetic Studies with Clinical Relevance

“…On the basis of the kinetic results obtained in this study, other conclusions can be drawn regarding the clinical pharmacokinetics of TREO, which is described by a two‐compartment model. The rate constant determined for TREO → S,S‐EBDM ( k 1 = 0.45 ± 0.04 h −1 ) is higher than the rate constant of the drug elimination phase (β) observed in patients, that is, 0.30–0.38 h −1 , which may seem surprising . However, β is a secondary hybrid of the three primary rate constants k 10 , k 12 , and k 21 that describe the elimination of the drug from the central compartment, distribution from the central compartment to the peripheral one, and distribution from the peripheral compartment to the central one, respectively.…”

“…In this study, we investigated the transformation of TREO into its biologically active epoxides, S,S‐EBDM and S,S‐DEB, in buffers with a constant pH of 7.4 at 37°C but with various ionic strengths to confirm the effect of electrolytes on the reaction kinetics. The initial concentration of TREO in the solutions, which was equal to 0.5, 1.0, and 2.5 mM, corresponded to the maximal concentration of the drug in plasma noted after 2 h infusion of the drug at a dose of 8 g/m 2 (0.6 ± 0.1 mM) and 10−14 g/m 2 (0.9−1.2 mM) in adults and 12−14 g/m 2 in children (2.0−3.1 mM) …”

“…In this buffer, the formation of S,S‐EBDM and S,S‐DEB in the two‐step TREO activation ( k 1 0.45 h −1 ; k 2 0.21 h −1 ) occurred five to 15 times faster than their hydrolytic decomposition ( k M 0.027 h −1 ; k D 0.045 h −1 ). Therefore, the very low S,S‐EBDM concentrations and undetectable S,S‐DEB levels in the plasma of patients treated with TREO cannot result from their slow formation or fast nonenzymatic hydrolysis in the presence of electrolytes specific to human plasma . However, other causes should be considered including a large distribution volume of S,S‐EBDM and S,S‐DEB.…”