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

• Published in: Cancer chemotherapy and pharmacology 2009-07, Vol.64 (3), p.641-645
• Main Authors: Amory, John Kenneth, Leonard, Thomas W, Page, Stephanie T, O'Toole, Edel, McKenna, Michael J, Bremner, William J
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Antineoplastic agents; Biological and medical sciences; Biological Availability; Cancer Research; Dose-Response Relationship, Drug; Fatty Acids - administration & dosage; Follicle Stimulating Hormone - blood; Gonadotropin-Releasing Hormone - antagonists & inhibitors; Gynecology. Andrology. Obstetrics; Humans; Luteinizing Hormone - blood; Luteinizing Hormone - drug effects; Male; Male genital diseases; Medical sciences; Medicine; Medicine & Public Health; Nephrology. Urinary tract diseases; Oligopeptides - administration & dosage; Oligopeptides - adverse effects; Oligopeptides - pharmacokinetics; Oncology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Prostatic Neoplasms - drug therapy; Short Communication; Tablets; Testosterone - blood; Time Factors; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Young Adult
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-009-1038-1

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.