Oral administration of the GnRH antagonist acyline, in a GIPET-enhanced tablet form, acutely suppresses serum testosterone in normal men: single-dose pharmacokinetics and pharmacodynamics.

Abstract

PURPOSE:

GnRH analogs are useful for the treatment of prostate cancer, but require parenteral administration. The peptide GnRH antagonist acyline potently suppresses luteinizing hormone (LH) and testosterone in man; however, its clinical utility is limited by the requirement for frequent injections. The use of a proprietary enhancer system called GIPET, which is based on medium-chain fatty acids, facilitates the oral bioavailability of peptides. We hypothesized that GIPET enhancement would allow for the safe oral dosing of acyline for the treatment of prostate cancer.

METHODS:

We enrolled eight healthy young men in a pharmacokinetic and pharmacodynamic study of 10, 20 and 40 mg doses of GIPET-enhanced oral acyline. Blood for measurement of serum LH, FSH, testosterone and acyline was obtained prior to each dose of GIPET-enhanced oral acyline and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48 h after dosing.

RESULTS:

Serum LH, FSH and serum testosterone were significantly suppressed by all doses of GIPET-enhanced oral acyline after 6 h, with suppression reaching a nadir 12 h after dosing. In addition, the 20 and 40 mg doses demonstrated sustained suppression of testosterone for 12-24 h. All hormone concentrations returned to normal 48 h after administration. There were no treatment-related serious adverse events, and laboratory assessments, including liver function tests and creatinine, were unaffected by treatment.

CONCLUSIONS:

Oral administration of GIPET-enhanced acyline significantly suppresses testosterone and gonadotropins in normal men without untoward side effects and might have utility in the management of prostate cancer.

• Authors: John Kenneth Amory, Thomas W Leonard, Stephanie T Page, Edel O'Toole, Michael J McKenna, William J Bremner
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 64 Issue 3 Pg. 641-5 (Aug 2009) ISSN: 1432-0843 [Electronic] Germany
• PMID: 19479252 (Publication Type: Controlled Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids
• Oligopeptides
• Tablets
• Gonadotropin-Releasing Hormone
• Testosterone
• Luteinizing Hormone
• Follicle Stimulating Hormone
• acyline

Topics

• Administration, Oral
• Adult
• Biological Availability
• Dose-Response Relationship, Drug
• Fatty Acids (administration & dosage)
• Follicle Stimulating Hormone (blood)
• Gonadotropin-Releasing Hormone (antagonists & inhibitors)
• Humans
• Luteinizing Hormone (blood, drug effects)
• Male
• Oligopeptides (administration & dosage, adverse effects, pharmacokinetics)
• Prostatic Neoplasms (drug therapy)
• Tablets
• Testosterone (blood)
• Time Factors
• Young Adult