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.

Fig. 1

Serum luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone in eight normal men administered increasing doses of 10, 20 and 40 mg of GIPET^®-enhanced oral acyline. All values are means ± SEM. Asterisk P < 0.05 compared with baseline; phi P < 0.05 compared with 10-mg dose. Dotted lines represent the upper and lower limit of the normal range in 100 normal men. Please note that the X-axis is non-linear