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

• DOI: 10.1016/j.ejps.2014.12.010
• Publication Date: 2014-12-16T17:48:36Z
• Authors: Franciszek Główka; Anna Kasprzyk; Michał Romański; Tomasz Wróbel; Jacek Wachowiak; Dawid Szpecht; Krzysztof Kałwak; Anna Wiela-Hojeńska; Paulina Dziatkiewicz; Artur Teżyk; Czesław Żaba
• Keywords: Male; Transplantation Conditioning; Adolescent; Hematopoietic Stem Cell Transplantation; Infant; Myeloablative Agonists; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Area Under Curve; Child, Preschool; Epoxy Compounds; Humans; Female; Prodrugs; Child; Busulfan

Pro-drug treosulfan (TREO) is currently evaluated in randomized phase III clinical trials as a conditioning agent prior to HSCT. In the present paper pharmacokinetics of both TREO and its biologically active monoepoxide (S,S-EBDM) was investigated in pediatric patients for the first time. The studies were carried out in 16 children (median age 7.5 years) undergoing TREO-based preparative regimen prior to HSCT, who received 10, 12 or 14 g/m(2) of the drug as a 1h or 2h intravenous infusion. Plasma concentrations of TREO as well as S,S-EBDM were determined using the validated HPLC-MS/MS method. The changes in S,S-EBDM concentration over time followed TREO levels. The area under the curve (AUC) of TREO was 100-fold higher than AUC of S,S-EBDM. No statistically significant dependency of the dose-normalized AUC of either TREO or S,S-EBDM on the patients' age and body surface area was stated. Moreover, plasma C(max) as well as AUC of S,S-EBDM demonstrated linear correlation with the C(max) and AUC of TREO, respectively. The biological half-lives of TREO and S,S-EBDM were similar. This indicates that S,S-EBDM was completely eliminated from the patients' blood within relatively short time, comparable to TREO.