Novel formulations of cetrorelix acetate in healthy men: pharmacodynamic effects and noncompartmental pharmacokinetics

The objective of this study was to investigate the effects on the pharmacodynamics and noncompartmental pharmacokinetics after weekly subcutaneous administration of novel formulations of cetrorelix acetate in healthy men. In a randomized parallel-group study, single subcutaneous doses of cetrorelix acetate (concentration: 2.5 mg peptide base/ml) dissolved in aqueous gluconic acid (CET/glu, dose: 5 or 10 mg peptide base) or in water (CET/wat, dose: 10 mg peptide base) were given to 36 subjects once weekly in the morning for 4 weeks. Cetrorelix plasma, serum testosterone, luteinizing hormone, andfollicle-stimulating hormone concentrations were monitored after each administration for 1 week, with extensive profiling after the first and fourth administration. Cetrorelix plasma concentrations were analyzed by radioimmunoassay and serum hormone concentrations by enzyme immunoassays. At least half-maximum testosterone suppression started with all treatments within less than 1 day. Deepest and longest testosterone suppression was achieved by 10 mg CET/glu. Duration of atleasthalf-maximum suppression was after the first dose median of 82 hours and after the fourth dose median of 122 hours, respectively. Substantial suppression was also evidentfor luteinizing hormone (LH) and, to a lesser extent, forfollicle-stimulating hormone (FSH). On average, Cmax was nearly doubled after single and multiple doses, and AUC(tau) was increased by about 50% after single doses and about 30% after multiple doses of 10 mg CET/glu as compared to 10 mg CET/wat. For tmax and t1/2, no significant differences were found between formulations. It was concluded that testosterone suppression increased with weekly subcutaneous administrations of 10 mg CET/glu. Compared to CET/wat, bioavailability and duration of suppression were increased with CET/glu.