Pharmacokinetic and pharmacodynamic characteristics of ganirelix (Antagon/Orgalutran*). Part II. Dose-proportionality and gonadotropin suppression after multiple doses of ganirelix in healthy female volunteers

Objective: To assess the dose-proportionality and pharmacodynamic propertie s of multiple doses of ganirelix (Antagon/Orgalutran; NV Organon, Oss, the Netherlands). Design: Randomized, parallel, pharmacokinetic, and pharmacodynamic study. Setting: Phase I clinical research unit. Patient(s): Three groups of 15 healthy female volunteers of reproductive ag e. Intervention(s): Subcutaneous injections of 0.125 mg, 0.25 mg, or 0.50 mg o f ganirelix were given once daily for 7 days. Blood samples were taken to a ssess serum ganirelix, LW, FSH, and E-2 concentrations. Main Outcome Measure(s): Pharmacokinetic parameters and hormone suppression . Result(s): Steady-state levels were reached between days 2 and 3. Peak conc entrations, which occurred approximately 1 hour after dosing, increased in a dose-proportional manner and averaged 5.2 ng/mL, 11.2 ng/mL, and 22.2 ng/ mL for the 0.125-mg, 0.25-mg, and 0.50-mg doses, respectively. Correspondin g mean values for the area under the curve over one dosing interval (24 hou rs) were 33 ng.h/mL, 77.1 ng.h/mL, and 137.8 ng h/mL, respectively. After t he last 0.25-mg dose of ganirelix, serum LH, FSH, and E-2 concentrations we re maximally decreased (by 74%, 32%, and 25% at 4 hours, 16 hours, and 16 h ours after injection, respectively). Serum hormone levels returned to pretr eatment values within 2 days after the last injection. Conclusion(s): The pharmacokinetics of ganirelix were dose-proportional wit hin the dose range studied. Multiple injections resulted in immediate suppr ession of gonadotropins, which was rapidly reversed after treatment discont inuation. ((C)1999 by American Society for Reproductive Medicine.).