Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients.

Abstract

4-Hydroxyandrostenedione (CGP32349; 4-OHA) is a clinically effective treatment for advanced postmenopausal breast cancer by both the parenteral and p.o. routes, as a result of its inhibition of aromatase and consequent suppression of plasma estrogen levels. Thirty patients were randomized to treatment with 250 mg 4-OHA orally once, twice, and 4 times daily for 2 weeks and 29 of these plus a further 11 patients were then randomized to treatment with 250 or 500 mg i.m. every 2 weeks to determine the optimal dose for each route according to the suppression of serum estradiol levels. There was no significant difference between the 3 oral doses in their suppression of estradiol levels indicating that the maximum required p.o. dose of 4-OHA is probably 250 mg daily. Suppression by the parenteral dose of 250 mg every 2 weeks was marginally suboptimal but clinical considerations of response and tolerability indicate this as the optimal dose for i.m. injection. 4-OHA had no effect on serum levels of androstenedione, testosterone, or 5 alpha-dihydrotestosterone when given by either route but p.o. treatment with 4 doses of 250 mg daily reduced sex hormone-binding globulin levels by a mean of 34%. Serum levels of estrone as measured by gas chromatography-mass spectrometry were suppressed to approximately 40% of baseline by parenteral treatment. The half-life of 4-OHA p.o. was approximately 3 h, whereas the apparent half-life of injected drug was between 5 and 10 days after a more rapid clearance during the first 4 days after injection.

• Authors: M Dowsett, D C Cunningham, R C Stein, S Evans, L Dehennin, A Hedley, R C Coombes
• Journal: Cancer research (Cancer Res) Vol. 49 Issue 5 Pg. 1306-12 (Mar 01 1989) ISSN: 0008-5472 [Print] United States
• PMID: 2917360 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial)

Chemical References

• Sex Hormone-Binding Globulin
• Estrone
• Androstenedione
• Estradiol
• formestane

Topics

• Administration, Oral
• Androstenedione (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
• Breast Neoplasms (blood, drug therapy)
• Dose-Response Relationship, Drug
• Estradiol (blood)
• Estrone (blood)
• Female
• Half-Life
• Humans
• Injections, Intramuscular
• Menopause
• Sex Hormone-Binding Globulin (analysis)