Luprodex Mechanism of Action

Pharmacology: Leuprolide Acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Human studies indicate that following an initial stimulation of gonadotropins, chronic stimulation with Leuprolide Acetate results in suppression or "down-regulation" of these hormones and consequent suppression of ovarian and testicular steroidogenesis. These effects are reversible on discontinuation of drug therapy.
Pharmacodynamics: 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, both in females and males. Continuous administration of Leuprorelin acetate results in decreased levels of LH and FSH. In men serum testosterone levels, initially raised in response to early luteinising hormone (LH) release, fall to castrate levels in about 2-4 weeks. Estradiol levels will decrease to postmenopausal levels in premenopausal women within one month of initiating treatment.
No pharmacodynamic studies have been conducted for Leuprorelin Acetate (Luprodex) 3.75 mg Depot from the literature following data were obtained.
Leuprorelin acetate when administered in males, testosterone is reduced to below castrate threshold (≤ 50 ng/dL). These decreases occur within three to five weeks after initiation of treatment. In a study, mean testosterone levels at six months was 10.1 (± 0.7) ng/dL, comparable to levels following bilateral orchiectomy. All patients who received the full dose of 22.5 mg Leuprorelin reached castrate levels at 5 weeks; 99 % had reached this by day 28. In the vast majority of patents, the testosterone levels seen were below 20 ng/dL. Prostate specific antigen (PSA) levels decreased by 98% over six months.
A study compared the efficacy and safety of the 3.75 mg and 11.25 mg depots of Leuprorelin acetate in advance and metastatic prostate cancer. Mean serum testosterone level fell below the threshold for chemical castration (0.5 ng/ml) at one month of treatment, continuing to decrease thereafter and stabilising at a value below the castration threshold. The decline in serum PSA mirrored that of serum testosterone in both groups. Long-term studies have shown that continuation of therapy maintains testosterone below the castrate level for up to seven years, and presumably indefinitely.
A long-term efficacy and safety of Leuprorelin acetate was assessed in patients with metastatic prostate cancer. Testosterone levels were maintained below the castrate threshold over the 63-month follow up period. Median survival time exceeded 42.5 months for those receiving monotherapy and 30.9 months for those receiving Leuprorelin acetate in combination with anti-androgens (this difference relating to baseline differences between groups).
Pharmacokinetics: Leuprorelin Acetate is not active when given orally.
Absorption: Intramuscular injection of the depot formulation provides plasma concentrations of Leuprorelin over a period of one month.
Distribution: Distributed to kidney, liver, pineal and pituitary tissues.
Metabolism: It is metabolized to its metabolites in hypothalamus and anterior pituitary gland.
Elimination: Leuprorelin is eliminated by enzymatic breakdown and renal excretion.
No pharmacokinetic studies have been conducted for Leuprorelin Acetate (Luprodex) 3.75 mg Depot.
Literature data indicates that Leuprorelin acetate is well absorbed after subcutaneous and intramuscular injections. Leuprorelin acetate binds to the LHRH receptors and is rapidly degraded. An initially high plasma level of Leuprorelin acetate peaks at around 3 hours after a subcutaneous injection, followed by a decrease to maintenance levels in 7 to 14 days. Leuprorelin acetate provides continuous plasma levels for up to 117 days resulting in suppression of testosterone to below castration level within 4 weeks of the first injection in the majority of patients. The metabolism, distribution and excretion of Leuprorelin acetate in humans have not been fully determined.
A study which included 3.75, 7.5, 11.25, 15 and 30 mg depots of Leuprorelin Acetate showed that a mean C_max of 13.1, 20.8 to 21.8, 47.4, 54.5 and 53 mcg/L, respectively, occur within 1 to 3 hours of depot subcutaneous administration. The plasma concentration was maintained between 0.4 and 1.4 mcg/L over 28 days after single 3.75, 7.5 or 15 mg depot injections.
A significant dose-related increase in the AUC from 0 to 35 days was noted after depot injection of Leuprorelin 3.75, 7.5 and 15 mg. Mean volume of distribution of Leuprorelin is was 36, 33 and 27 L after depot administration of 3.75, 7.5 and 15 mg, respectively. Total body clearance is 9.1 L/h and elimination half-life 3.6 hours after a subcutaneous 1 mg injection; corresponding values after intravenous injection are 8.3 L/h and 2.9 hours.
In Children: The Leuprorelin serum levels in children during the first 6 months of treatment following s.c. administration of Leuprorelin acetate 3-month depot (two injections) showed following results.
From the first injection, the Leuprorelin serum levels increase reaching maximal serum levels at month 4 (294.79 pg/ml ± 105.42) and slightly decrease until month 6 (229.02 pg/ml ± 103.33).