title: Pharmacokinetics of treosulfan and its active monoepoxide in pediatric patients after intravenous infusion of high-dose treosulfan prior to HSCT.
abstract: 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.
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland. Electronic address: glowka@ump.edu.pl.
authors.forename: Franciszek
authors.initials: F
authors.lastname: Główka
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kasprzyk
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Romański
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wróbel
authors.affiliation: Department of Oncology, Hematology and Pediatric Transplantation, Poznan University of Medical Sciences, 27/33 Szpitalna Street, 60-572 Poznań, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Wachowiak
authors.affiliation: Department of Oncology, Hematology and Pediatric Transplantation, Poznan University of Medical Sciences, 27/33 Szpitalna Street, 60-572 Poznań, Poland.
authors.forename: Dawid
authors.initials: D
authors.lastname: Szpecht
authors.affiliation: Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation, Wroclaw Medical University, 44 Bujwida Street, 50-368 Wroclaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kałwak
authors.affiliation: Department of Clinical Pharmacology, Wroclaw Medical University, 211a Borowska Street, 50-556 Wroclaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wiela-Hojeńska
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Dziatkiewicz
authors.affiliation: Department of Forensic Medicine, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Teżyk
authors.affiliation: Department of Forensic Medicine, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland.
authors.forename: Czesław
authors.initials: C
authors.lastname: Żaba
mesh_terms: D000293:Adolescent; D019540:Area Under Curve; D002066:Busulfan / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004852:Epoxy Compounds / Q000097:blood; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D019653:Myeloablative Agonists / Q000097:blood / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics*; D019172:Transplantation Conditioning
chemical_list: D004852:Epoxy Compounds; D019653:Myeloablative Agonists; D011355:Prodrugs; C018404:treosulfan; D002066:Busulfan
keywords: (2S,3S)-1,2:3,4-Diepoxybutane (PubChem CID: 91595); Children; HPLC–MS/MS; Monoepoxide; Myeloablative conditioning; Pro-drug; Treosulfan (PubChem CID: 9882105)