Investigation of bioavailability and pharmacokinetics of treosulfan capsules in patients with relapsed ovarian cancer

Purpose: Treosulfan (L-threitol-1,4-bis-methanesulfonate, Ovastat) is a pro drug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcino ma were treated with alternating doses of oral and intravenous (i.v.) treos ulfan of 1.5 or 2.0 g daily for 5 to 8 days. Methods: A sensitive method fo r the determination of treosulfan in plasma and urine by reversed-phase hig h-performance liquid chromatography had previously been developed. Pharmaco kinetic analyses of treosulfan were carried on plasma and urine samples fro m 20 i.v. courses and 20 courses of oral administration. Results: The bioav ailability ratio (f) of oral to i.v. administration was calculated as 0.97 +/- 0.18 (mean +/- SD) using the values AUC(oral) = 82.1 +/- 39.4 mu g/ml h and AUC(i.v.) = 85.4 +/- 30.3 mu g/ml h. The peak plasma concentration c(m ax) (29 +/- 14 mu g/ml vs 65 +/- 23 mu g/ml) was significantly (P < 0.01) h igher after i.v. administration and the t(max) after oral administration wa s 1.5 +/- 0.33 h. The terminal half-life of treosulfan was about 1.8 h. The mean urinary excretion of the parent compound was about 15% of the adminis tered total dose over 24 h (range 6-26%). Conclusions: The high and relativ ely constant bioavailability of treosulfan indicates that capsules provide a satisfactory noninvasive treatment alternative. A feasible and reliable o ral treosulfan formulation could provide the basis for the development of l ong-term low-dose outpatient treatment of patients with malignant diseases.