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

Abstract

Treosulfan (TREO) is currently investigated as an alternative treatment of busulfan in conditioning before hematopoietic stem cell transplantation. The knowledge of the blood-brain barrier penetration of the drug is still scarce. In this paper, penetration of TREO and its active monoepoxide (S,S-EBDM) and diepoxide (S,S-DEB) into the CNS was studied in juvenile (JR) and young adult rats (YAR) for the first time. CD rats of both sexes (n = 96) received an intravenous dose of TREO 500 mg/kg b.wt. Concentrations of TREO, S,S-EBDM, and S,S-DEB in rat plasma, brain, and cerebrospinal fluid (CSF, in YAR only) were determined by validated bioanalytical methods. Pharmacokinetic calculations were performed in WinNonlin using a noncompartmental analysis and statistical evaluation was done in Statistica software. In male JR, female JR, male YAR, and female YAR, the brain/plasma area under the curve (AUC) ratio for unbound TREO was 0.14, 0.17, 0.10, and 0.07 and for unbound S,S-EBDM, it was 0.52, 0.48, 0.28, and 0.22, respectively. The CSF/plasma AUC ratio in male and female YAR was 0.12 and 0.11 for TREO and 0.66 and 0.64 for S,S-EBDM, respectively. Elimination rate constants of TREO and S,S-EBDM in all the matrices were sex-independent with a tendency to be lower in the JR. No quantifiable levels of S,S-DEB were found in the studied samples. TREO and S,S-EBDM demonstrated poor and sex-independent penetration into CNS. However, the brain exposure was greater in juvenile rats, so very young children might potentially be more susceptible to high-dose TREO-related CNS exposure than young adults.

Treosulfan Pharmacokinetics and its Variability in Pediatric and Adult Patients Undergoing Conditioning Prior to Hematopoietic Stem Cell Transplantation: Current State of the Art, In-Depth Analysis, and Perspectives

“…These results led to the conclusion that very young patients receiving high-dose treosulfan prior to HSCT may experience higher neurotoxicity than older patients due to the increased penetration of the prodrug and S,S-EBDM across the incompletely mature blood-brain barrier. This corresponded to the results obtained in clinical studies in which seizures only occurred in patients under 4 months of age [ 8 , 18 ].…”

“…To date, the binding of treosulfan to human plasma and tissue proteins has not been examined under physiological pH to avoid the epoxy transformation of the parent drug. However, it is worth noting that the drug recovery from acidified human plasma after 10 kDa ultrafiltration cut-off was 96 ± 4% [ 31 ], and its unbound fraction in acidified rat plasma and tissue homogenates exceeded 0.94 [ 18 , 19 ]. Moreover, the in vivo ratio of the area under the curve (AUC) of treosulfan in rat liver, lungs, muscle, and bone marrow to its AUC in plasma ranged from 0.8 to 1.0 [ 19 ].…”

Bone Marrow-Derived Cell Accumulation in the Spinal Cord Is Independent of Peripheral Mobilization in a Mouse Model of Amyotrophic Lateral Sclerosis

“…Based upon its hydrophilicity, TREO would not be predicted to readily cross the BBB and gain access to the CNS. In support of this claim, little penetrance of TREO and its active metabolites were detectable within the CNS of rats administered 500 mg/kg TREO, and limited amounts of TREO crossed an in vitro BBB model (20, 21). Virtually, all of the BMDCs detectable in TREO-conditioned mice had morphologies suggesting blood vessel-associated localizations (Table 1).…”

“…Treosulfan (TREO; Medac, DE), a hydrophilic analog of BU that does not readily cross the BBB (20, 21), was resuspended in sterile ddH 2 O at a concentration of 50 mg/mL just prior to administration. Doses were selected based upon previous studies by Van Pel et al and Nasa et al (22, 23).…”

In Vivo Red Blood Cells/Plasma Partition Coefficient of Treosulfan and Its Active Monoepoxide in Rats

“…Treosulfan and S,S-EBDM very weakly bind to rat plasma (unbound fraction ≥ 0.94) and only free drug molecules in plasma partition into RBC [ 19 , 21 ]. Therefore, the K e/p of treosulfan and S,S-EBDM was calculated as the ratio of the total concentrations of the analyte determined in the RBC lysate and plasma ( C e / C p ) [ 21 ].…”