Eligard Mechanism of Action

Pharmacotherapeutic group: Gonadotropin releasing hormone analogues. ATC code: L02A E02.
Pharmacology: Pharmacodynamics: Leuprorelin acetate is a synthetic nonapeptide agonist of naturally occurring gonadotropin releasing hormone (GnRH) that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular steroidogenesis in males. This effect is reversible upon discontinuation of medicinal product therapy. However, the agonist possesses greater potency than the natural hormone and the time to recovery of testosterone levels may vary between patients.
Administration of leuprorelin acetate results in an initial increase in circulating levels of luteinising hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids, testosterone and dihydrotestosterone in males. Continuous administration of leuprorelin acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to below castrate threshold (≤ 50 ng/dL).
ELIGARD 7.5 mg: These decreases occur within three to five weeks after initiation of treatment. Mean testosterone levels at six months are 6.1 (± 0.4) ng/dL, comparable to levels following bilateral orchiectomy. All patients in the pivotal clinical study reached castrate levels at 6 weeks; 94% had reached this by day 28 and 98% by day 35. In the vast majority of patients the testosterone levels seen were below 20 ng/dL although the full benefit of these low levels has not yet been established. PSA levels decreased by 94% over six months.
ELIGARD 22.5 mg: These decreases occur within three to five weeks after initiation of treatment. Mean testosterone levels at six months are 10.1 (± 0.7) ng/dL, comparable to levels following bilateral orchiectomy. All patients who received the full dose of 22.5 mg leuprorelin in the pivotal clinical study reached castrate levels at 5 weeks; 99% had reached this by day 28. In the vast majority of patients the testosterone levels seen were below 20 ng/dL although the full benefit of these low levels has not yet been established. PSA levels decreased by 98% over six months.
ELIGARD 45 mg: These decreases occur within three to four weeks after initiation of treatment. Mean testosterone levels at six months are 10.4 (± 0.53) ng/dL, comparable to levels following bilateral orchiectomy. All but one patient who received the full dose of 45 mg leuprorelin in the pivotal clinical study reached castrate levels at 4 weeks. In the vast majority of patients the testosterone levels seen were below 20 ng/dL although the full benefit of these low levels has not yet been established. PSA levels decreased by 97% over six months.
Long-term studies have shown that continuation of therapy maintains testosterone below the castrate level for up to seven years, and presumably indefinitely.
Tumour size was not measured directly during the clinical trial programme, but there was an indirect beneficial tumour response as shown by a 94% reduction in mean PSA for ELIGARD 7.5 mg, 98% reduction for ELIGARD 22.5 mg and 97% reduction for ELIGARD 45 mg.
Pharmacokinetics: Absorption: ELIGARD 7.5 mg: In patients with advanced carcinoma of the prostate, mean serum leuprorelin concentrations following the initial injection rise to 25.3 ng/ml at 4-8 hr (Cmax) after injection. After the initial increase following each injection (the plateau phase from 2-28 days after each dose), serum concentrations remain relatively constant (0.28 - 1.67 ng/ml). There is no evidence of accumulation during repeated dosing.
ELIGARD 22.5 mg: In patients with advanced carcinoma of the prostate, mean serum leuprorelin concentrations following the initial injection rise to 127 ng/ml at 4.6 hr (Cmax) after injection. After the initial increase following each injection (the plateau phase from 3 - 84 days after each dose), serum concentrations remained relatively constant (0.2 - 2 ng/ml). There is no evidence of accumulation during repeated dosing.
ELIGARD 45 mg: In patients with advanced carcinoma of the prostate, mean serum leuprorelin concentrations following the initial injection rise to 82 ng/ml at 4.4 hr (Cmax) after injection. After the initial increase following each injection (the plateau phase from 3 - 168 days after each dose), serum concentrations remained relatively constant (0.2 - 2 ng/ml). There is no evidence of accumulation during repeated dosing.
Distribution: The mean steady-state volume of distribution of leuprorelin following intravenous bolus administration to healthy male volunteers was 27 litres. In vitro binding to human plasma proteins ranged from 43% to 49%.
Elimination: In healthy male volunteers, a 1 mg bolus of leuprorelin acetate administered intravenously revealed that the mean systemic clearance was 8.34 l/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.
No excretion studies have been conducted with ELIGARD.
No drug metabolism study was conducted with ELIGARD.
Toxicology: Preclinical safety data: Preclinical studies with leuprorelin acetate, revealed in both sexes effects on the reproductive system, including atrophy of the reproductive organs and suppression of reproductive function, which were expected from the known pharmacological properties. These effects were shown to be reversible after discontinuation of the treatment and an appropriate period of regeneration. Leuprorelin acetate did not show teratogenicity. Embryotoxicity/lethality was observed in rabbits, in line with the pharmacological effects of leuprorelin acetate on the reproductive system.
Carcinogenicity studies were performed in rats and mice over 24 months. In rats, a dose-related increase in pituitary apoplexy was observed after subcutaneous administration at doses of 0.6 to 4 mg/kg/day. No such effect was observed in mice.
Leuprorelin acetate and related one-month product ELIGARD 7.5 mg were not mutagenic in a set of in vitro and in vivo assays.