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.

Restoration of Rat Colonic Epithelium After In Situ Intestinal Instillation of the Absorption promoter, Sodium Caprate

“…Transiently increasing transmucosal permeability with C 10 is accompanied by superficial mucosal injury. The intestinal epithelium has the capacity to rapidly recover from any mucosal damage sustained by treatment with C 10 . This provides further evidence that the enhancement action and damage caused by mild non-ionic surfactants like C 10 are closely related in vivo, but whether this is a significant safety issue is debatable.…”

“…In preclinical studies, C 10 improved oral macromolecule permeation across Caco-2 monolayers [4], isolated rat and human intestinal mucosa [5], as well as in rat intestinal instillations and perfusions [6]. Recently, the effect of the promoter on oral bioavailability has been successfully demonstrated in man for enteric coated solid-dosage forms with a range of actives including antisense oligonucleotides [7], bisphosphonates [8], low molecular weight heparin [9] and the GnRH antagonist, acyline [10].…”

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

“…In a subsequent human trial, single dose administration of acyline in a GIPET® formulation suppressed serum gonadotropin and testosterone biosynthesis in normal men [228]. In a Phase I study, GIPET® also improved the oral F of the bisphosphonate, alendronate, 12-fold compared to alendronate sodium tablets (Fosamax®, Merck), to yield an oral F of 7.2 % based on urinary excretion data of the unchanged molecule [24,229].…”

“…In a total of 16 Phase I studies involving 300 volunteers, some 800 exposures to GIPET® did not induce measureable toxicity; indeed in some cases individual patients were safely dosed up to six times each [24]. In routine blood biochemical assessments, a single dose administration of GIPET® to healthy volunteers did not lead to abnormal haematology, clinical chemistry or hepatic function [228]. In the Phase II study of Orazol® referred to above, GIPET® was administered once weekly for 8 weeks and was well tolerated with no abnormalities in urinalysis, haematology or clinical chemistry.…”

GnRH-Analoga in der Reproduktionsmedizin

“…Oral verfügbare GnRH-Antagonisten werden als Alternative zur schmerzhaften Depotinjektion von GnRH-Agonisten bzw. als Alternative zur langfristig täglichen subkutanen oder intranasalen Anwendung von GnRH-Agonisten erforscht [2]. Die Entwicklung von oral verfügbaren GnRH-Antagonisten befindet sich in der klinischen Phase II.…”