Luprolex Mechanism of Action

Pharmacology: Mechanism of action: 1.88 mg and 3.75 mg: Repeated administration of either LH-RH in a massive dose or leuprorelin acetate, which is a highly potent LH-RH derivative, causes a transient pituitary-gonad system stimulating effect (acute effect) immediately after the first administration and then suppresses both the production and release of gonadotropin in the pituitary. It further suppresses the response of the ovary and testis to gonadotropin, resulting in a decrease in estradiol and testosterone producing action (chronic effect). The LH releasing activity of Leuprorelin Acetate is approximately equal to 100 times that of LH-RH, and its action of suppressing the pituitary-gonad function is stronger than that of LH-RH. Since Leuprorelin Acetate is a highly potent LH-RH derivative, its strong action of suppressing the pituitary-gonad function is attributed to its higher resistance to proteolytic enzymes and higher affinity for LH-RH receptors in comparison with LH-RH. Moreover, since Leuprorelin (Luprolex) is a sustained release preparation, it constantly releases Leuprorelin Acetate into the blood to effectively reduce the response of the ovary and testis, producing a highly favorable pituitary-gonad inhibitory action.
11.25 mg: Leuprolide acetate, a GnRH agonist, acts as an inhibitor of gonadotropin secretion. Animal studies indicate that following an initial stimulation, continuous administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect was reversible upon discontinuation of drug therapy.
Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs.
1.88 mg and 3.75 mg: Action on gonadotropic hormone suppression: In patients with endometriosis, uterine myoma or premenopausal breast cancer, subcutaneous injection of Leuprorelin Acetate once every 4 weeks generally causes serum estradiol to fall to a value near the menopausal level. Thus, this drug produces an ovarian function suppressing effect, with resultant inhibition of normal ovulation and cessation of menstruation.
In patients with prostate cancer, subcutaneous administration of Leuprorelin Acetate once every 4 weeks causes serum testosterone to fall below the castration level, indicating a pharmacological castrating effect.
In girl and boy patients with central precocious puberty, subcutaneous administration of leuprorelin acetate, once every 4 weeks, reduces the serum level of gonadotropic hormone to the prepubertal level, exhibiting an action of delaying the progression of secondary sex characteristics.
Pharmacodynamics: 11.25 mg: In humans, administration of leuprolide acetate results in an initial increase in circulating concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in concentrations of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased concentrations of LH and FSH. In males, testosterone is reduced to castrate concentrations. In premenopausal females, estrogens are reduced to postmenopausal concentrations. These decreases occur within two to four weeks after initiation of treatment, and castrate concentrations of testosterone in prostatic cancer patients have been demonstrated for more than five years.
Leuprolide acetate is not active when given orally.
Pharmacokinetics: Special Populations: The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined.
Endometriosis: Blood concentrations: Figure 1 shows blood concentration in a study in which 1.88 mg or 3.75 mg, as Leuprorelin (Luprolex), was administered subcutaneously to patients with endometriosis in a total of six times at 4-week intervals. When 3.75 mg, as Leuprorelin (Luprolex), was administered subcutaneously to patients with endometriosis (77 patients) six times at 4-week intervals, the combined blood concentration of the unchanged compound and metabolite M-I* revealed no accumulation.
*M-I: Tyr - D - Leu - Leu - Arg - Pro - NHC2H5. (See Figure 1.)

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Urinary excretion: The following table shows the urinary excretion rates (%) of the unchanged compound and metabolite M-I at 24 hours after the first administration and 24 hours after the sixth administration, when 3.75 mg, as Leuprorelin (Luprolex), was administered subcutaneously to patients with endometriosis six times at 4-week intervals.
Uterine fibroids: The pharmacokinetics in patients with uterine myoma are considered to be the same as those in patients with endometriosis, which is the same estrogen dependent disease as uterine myoma and is occurring in nearly the same age group as uterine myoma.
Central precocious puberty: Blood concentrations: Figure 2 shows the blood concentrations of the unchanged compound after the first administration, when 30 μg/kg, as Leuprorelin (Luprolex), was given subcutaneously to patients with central precocious puberty twelve times at 4-week intervals. Judging from the trend of blood concentration of the unchanged compound, this drug is not considered to accumulate. (See Figure 2.)

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Urinary excretion: When a single dose of 30 μg/kg, as Leuprorelin (Luprolex), was subcutaneously administered to patients with central precocious puberty (1 patient), the urinary excretion rates of the unchanged compound and its metabolite M-I up to 28 days after administration were 1.8% and 7.1%, respectively.
Absorption: 3.75 mg: A single dose of Leuprorelin (Luprolex) 3.75 mg was administered by intramuscular injection to healthy female volunteers. The absorption of leuprorelin was characterized by an initial increase in plasma concentration, with peak concentration ranging from 4.6 to 10.2 ng/mL at four hours postdosing. However, intact leuprorelin and an inactive metabolite could not be distinguished by the assay used in the study. Following the initial rise, leuprorelin concentrations started to plateau within two days after dosing and remained relatively stable for about four to five weeks with plasma concentrations of about 0.30 ng/mL.
11.25 mg: Following a single injection of the three month formulation of Leuprorelin (Luprolex) 11.25 mg in female subjects, a mean plasma leuprorelin concentration of 36.3 ng/mL was observed at 4 hours. Leuprorelin appeared to be released at a constant rate following the onset of steady-state levels during the third week after dosing and mean levels then declined gradually to near the lower limit of detection by 12 weeks. The mean (± standard deviation) leuprorelin concentration from 3 to 12 weeks was 0.23 ± 0.09 ng/mL. However, intact leuprorelin and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by the rapid decline to a steady-state level, was similar to the release pattern seen with the monthly formulation.
Distribution: 3.75 mg and 11.25 mg: The mean steady-state volume of distribution of leuprorelin following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.
Metabolism: 3.75 mg and 11.25 mg: In healthy male volunteers, a 1 mg bolus of leuprorelin administered intravenously 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.
In rats and dogs, administration of ¹⁴C-labeled leuprorelin was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized.
3.75 mg: The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprorelin concentrations.
11.25 mg: In a pharmacokinetic/pharmacodynamics study of endometriosis patients, intramuscular Leuprorelin (Luprolex) 11.25 mg every 12 weeks or intramuscular Leuprorelin (Luprolex) 3.75 mg every 4 weeks was administered for 24 weeks. There was no statistically significant difference in changes of serum estradiol concentration from baseline between the 2 treatment groups.
M-I plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprorelin concentrations.
Excretion: 3.75 mg and 11.25 mg: Following administration of Leuprorelin (Luprolex) 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.