Chemical formula: C₅₉H₈₄N₁₆O₁₂ Molecular mass: 1,209.398 g/mol
Leuprorelin is inactive when given orally due to poor membrane permeability and an almost complete inactivation by intestinal proteolytic enzymes.
Leuprorelin has potent LHRH agonist properties when given during short-term and intermittent therapy, however, when administered in a continuous, nonpulsatile manner, LHRH analogs induce inhibition of gonadotropin secretion and suppression of testicular steroidogenesis.
Upon binding to pituitary LHRH receptors, leuprorelin produces an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to an acute rise in levels of testosterone and dihydrotestosterone. However, within five to eight days after drug administration, LHRH analogs produce desensitization of the LHRH receptor complex and/or downregulation of the anterior pituitary gland. Due to the fact that there are fewer receptors on the cell surface, cellular stimulation is decreased, and less gonadotropin is synthesized and secreted. Eventually, after several weeks of LHRH agonist therapy, LH and FSH secretion is suppressed. As a result, Leydig cells in the testes cease to produce testosterone, and the serum testosterone concentration declines to a castration level (less than 0.5 ng/mL) in about two to four weeks after initiation of treatment.
Reversible suppression of pituitary gonadotropin release occurs, with a subsequent decrease in oestradiol (E2) or testosterone levels to values in the pre-pubertal range.
Initial gonadal stimulation (flare-up) may cause vaginal bleeding in girls who are already post-menarchal at start of treatment. Withdrawal bleeding may occur at the start of treatment. The bleeding normally stops as treatment continues.
The following therapeutic effects can be demonstrated:
Treatment result is the suppression of the pathologically, prematurely activated hypothalamic-pituitary-gonadal axis according to pre-pubertal age.
In a long-term clinical trial in children treated with leuprorelin at doses up to 15mg monthly for >4 years resumption of pubertal progression were observed after cessation of treatment. Follow up of 20 female subjects to adulthood showed normal menstrual cycles in 80% and 12 pregnancies in 7 of the 20 subjects including multiple pregnancies for 4 subjects.
Leuprorelin is well absorbed after subcutaneous and intramuscular injections. It binds to the LHRH receptors and is rapidly degraded. An initially high plasma level of leuprorelin peaks at around 3 hours after a subcutaneous injection, followed by a decrease to maintenance levels in 7 to 14 days. Leuprorelin 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.
Following three once-monthly injections via the intramuscular route only in a sample of prostate cancer patients (N=12), maximal leuprorelin plasma concentration was similar among the three cycles. After first administration (Days 0-28), Cmax was 13,145.6±3,070.6 pg/ml. Median time to achieve Cmax (Tmax) was 0.04 days, corresponding to 0.96 h (range 0.96–4.08 h).
The metabolism, distribution and excretion of leuprorelin in humans have not been fully determined.
In healthy male volunteers, the mean steady-state volume of distribution of leuprorelin following bolus intravenous (IV) 1.0 mg dose was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.
Leuprorelin is expected to be metabolised to smaller inactive peptides that may be excreted or further catabolised.
In healthy male volunteers, a 1.0 mg bolus of leuprorelin administered IV revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.
Following administration of leuprorelin to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.
The pharmacokinetics of the drug in hepatically and renally impaired patients has not been determined.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity conducted with leuprorelin.
As expected from its known pharmacological properties, non-clinical studies showed effects on the reproductive systems, which were reversible. In the reproductive toxicity studies, leuprorelin did not show teratogenicity. However, embryotoxicity/lethality was observed in rabbits.
Animal studies have shown that leuprorelin has a high acute safety factor. No major overt toxicological problems have been seen during repeated administration. Whilst the development of pituitary adenomas has been noted in chronic toxicity studies at high doses in some animal species, this has not been observed in long-term clinical studies. No evidence of mutagenicity or teratogenicity has been shown. Animal reproductive studies showed increased foetal mortality and decreased foetal weights reflecting the pharmacological effects of this LHRH agonist.
Carcinogenicity studies performed in rats with leuprorelin administered subcutaneously (0.6 to 4 mg/kg/day), showed a dose-related increase in pituitary adenomas. Furthermore a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males was observed the highest incidence was in the low dose group. Administration of leuprorelin resulted in inhibition of the growth of certain hormone dependent tumours (prostatic tumours in Noble and Dunning male rats and DMBA-induced mammary tumours in female rats). No such effects were observed in carcinogenicity studies performed in mice.
Studies with leuprorelin showed that the product was not mutagenic in a set of in vitro and in vivo assays.
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