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

Treosulfan is a prodrug that undergoes a highly pH- and temperature-dependent nonenzymatic conversion to the monoepoxide {(2S,3S)-1,2-epoxy-3,4-butanediol 4-methanesulfonate [S,S-EBDM]} and diepoxide {(2S,3S)-1,2:3,4-diepoxybutane [S,S-DEB]}. Currently, treosulfan is tested in clinical trials as an alternative to busulfan in conditioning prior to hematopoietic stem cell transplantation (HSCT). Of note, the optimal dosing of the prodrug is still unresolved, especially in infants. In this paper, the pharmacokinetics of treosulfan, together with its biologically active epoxides, is comprehensively reviewed for the first time, with the focus on conditioning prior to HSCT. Most of the insightful data presented in this review comes from studies that have been conducted in the last 3years. The article widely discusses the volume of distribution and total clearance of treosulfan. In particular, the interindividual variability of these key parameters in infants, children above 1year of age, and adults is analyzed, including possible covariates. A clinically important aspect of the formation rate-limited elimination of S,S-EBDM and S,S-DEB is described, including the correlation between the exposure of the prodrug and S,S-EBDM in children. The significance of the elimination half-life of treosulfan and its epoxides for successful conditioning prior to HSCT is also raised. Furthermore, the organ disposition of treosulfan and S,S-EBDM in rats is discussed in the context of the clinical toxicity and myeloablative activity of treosulfan versus busulfan. Moreover, perspectives for future therapeutic drug monitoring of treosulfan are presented. The review is intended to be helpful to pharmacists and doctors in the comprehension of the clinical pharmacokinetics of treosulfan.