Clinical pharmacokinetics of intravenous treosulfan in patients with advanced solid tumors

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/m(2) 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/m(2) group and 7 were analyzed in the 10-g/m(2) 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 C-max values were significantly (P < 0.01) higher in the 10-g/m(2) group (AUC 708 +/- 168 versus 977 +/- 182 mu g ml(-1) h, C-max 465 +/- 98 versus 597 +/- 94 mu g/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/m(2) treosulfan using a 2-h infusion protocol.