&NA; Treosulfan (TREO), a structural analog of busulfan, is currently studied as a myeloablative agent in conditioning regimens before hematopoietic stem cell transplantation in pediatric patients. High exposure to TREO… Click to show full abstract
&NA; Treosulfan (TREO), a structural analog of busulfan, is currently studied as a myeloablative agent in conditioning regimens before hematopoietic stem cell transplantation in pediatric patients. High exposure to TREO (>1650 mg*h/mL) might be related to early toxicity, especially skin toxicity and mucositis. The aim of the present study was to investigate a potential relationship between exposure to TREO and its monoepoxytransformer (S,S‐EBDM), as well as variability of the pharmacokinetics of these entities by means of a population pharmacokinetic approach with a non‐linear mixed‐effects analysis. The study included data from 14 children with malignant and non‐malignant diseases treated with TREO in daily doses 10–14 g/m2. The parent‐metabolite population pharmacokinetic model was developed in NONMEM 7.3 software. Upon the constructed model, an extensive simulation was performed to assess the correlation between exposure to TREO and S,S‐EBDM. It was found that TREO and S,S‐EBDM pharmacokinetics was best described with 2‐compartmental and 1‐compartmental linear models, respectively. The vast majority (>65%) of TREO was transformed to S,S‐EBDM. Overall, a considerable interpatient variability of pharmacokinetic parameters was observed, especially the clearance of S,S‐EBDM. A weak correlation was found between the exposure to TREO and S,S‐EBDM (r = 0.1681, p < 0.0001). Also, patients with an exposure to TREO above 1650 mg*h/mL were most likely to have also a high exposure to S,S‐EBDM (35.38 &mgr;M*h vs. 43.14 &mgr;M*h, p < 0.0001). In summary, a parent‐metabolite population pharmacokinetic model for TREO and S,S‐EBDM was developed for the first time. It was shown that there is a weak correlation between exposure to TREO and S,S‐EBDM. Therefore therapeutic drug monitoring of not only prodrug but also its active epoxide might be needed. Graphical abstract Figure. No Caption available.
               
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