title: Clinical pharmacokinetics of intravenous treosulfan in patients with advanced solid tumors.
abstract: Treosulfan (L-threitol- 1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. For a clinical and pharmacology study, patients with advanced, refractory, or resistant solid tumors were treated with a single-dose intravenous 30-min infusion of 8 or 10 g/m2 treosulfan. A sensitive method for the determination of treosulfan in plasma and urine by reverse-phase high-performance liquid chromatography was developed. A total of 14 plasma and urine treosulfan pharmacokinetics determinations were analyzed in the 8-g/m2 group and 7 were analyzed in the 10-g/m2 group, the maximum tolerated dose for this group of pretreated patients. The terminal half-life of treosulfan was in the range of 1.8 h. AUC and Cmax values were significantly (P < 0.01) higher in the 10-g/m2 group (AUC 708+/-168 versus 977+/-182 microg ml(-1) h, Cmax 465+/-98 versus 597+/-94 microg/ml). The mean urinary excretion of the parent compound was about 25% of the total dose delivered over 48 h (range 5-49%), and about 20% was excreted during the first 6 h after administration. Currently, a clinical phase I pharmacokinetics and dose-escalation trial with autologous blood stem-cell support has been started at 20 g/m2 treosulfan using a 2-h infusion protocol.
authors.affiliation: Innere Klinik und Poliklinik (Tumorforschung), Universitätsklinikum Essen, Westdeutsches Tumorzentrum, Germany.
authors.forename: R A
authors.initials: RA
authors.lastname: Hilger
authors.forename: A
authors.initials: A
authors.lastname: Harstrick
authors.forename: W
authors.initials: W
authors.lastname: Eberhardt
authors.forename: C
authors.initials: C
authors.lastname: Oberhoff
authors.forename: M
authors.initials: M
authors.lastname: Skorzec
authors.forename: J
authors.initials: J
authors.lastname: Baumgart
authors.forename: S
authors.initials: S
authors.lastname: Seeber
authors.forename: M E
authors.initials: ME
authors.lastname: Scheulen
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002066:Busulfan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; C018404:treosulfan; D002066:Busulfan