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

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. In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcinoma were t...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 2000, Vol.45 (6), p.483-488
Main Authors: HILGER, R. A, JACEK, G, OBERHOFF, C, KREDTKE, S, BAUMGART, J, SEEBER, S, SCHEULEN, M. E
Format: Article
Language:English
Subjects:
Administration, Oral
Aged
Antineoplastic agents
Antineoplastic Agents, Alkylating - administration & dosage
Antineoplastic Agents, Alkylating - pharmacokinetics
Antineoplastic Agents, Alkylating - therapeutic use
Biological and medical sciences
Biological Availability
Busulfan - administration & dosage
Busulfan - analogs & derivatives
Busulfan - pharmacokinetics
Busulfan - therapeutic use
Chemotherapy
Dose-Response Relationship, Drug
Drug Evaluation
Female
Humans
Medical sciences
Middle Aged
Neoplasm Recurrence, Local
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - metabolism
Pharmacology. Drug treatments
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Summary: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. In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcinoma were treated with alternating doses of oral and intravenous (i.v.) treosulfan of 1.5 or 2.0 g daily for 5 to 8 days. A sensitive method for the determination of treosulfan in plasma and urine by reversed-phase high-performance liquid chromatography had previously been developed. Pharmacokinetic analyses of treosulfan were carried on plasma and urine samples from 20 i.v. courses and 20 courses of oral administration. The bioavailability 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 microg/ml h and AUC i.v. = 85.4 +/- 30.3 microg/ml h. The peak plasma concentration cmax (29 +/- 14 microg/ml vs 65 +/- 23 microg/ml) was significantly (P < 0.01) higher after i.v. administration and the tmax after oral administration was 1.5 +/- 0.34 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 administered total dose over 24 h (range 6-26%). The high and relatively constant bioavailability of treosulfan indicates that capsules provide a satisfactory noninvasive treatment alternative. A feasible and reliable oral treosulfan formulation could provide the basis for the development of long-term low-dose outpatient treatment of patients with malignant diseases.
ISSN:0344-5704
1432-0843
DOI:10.1007/s002800051023