Enantone L.P. Mechanism of Action

Pharmacotherapeutic group: Antineoplastics - Endocrine Therapy - GnRH analogues. ATC code: L02AE02.
Pharmacology: Pharmacodynamics: 3.75 mg/11.25 mg: Enantone L.P. 3.75 mg/11.25 mg contains leuprorelin acetate, a synthetic nonapeptide analogue of naturally occurring gonadotrophin-releasing hormone (GnRH) which possesses greater potency than the natural hormone. Leuprorelin acetate is a peptide and therefore, unrelated to the steroids. Chronic administration results in an inhibition of gonadotrophin production and subsequent suppression of ovarian and testicular steroid secretion. This effect is reversible on discontinuation of therapy.
Administration of leuprorelin acetate results in an initial increase in circulating levels of gonadotrophins which leads to a transient increase in gonadal steroid levels in both men and women. Continued administration of leuprorelin acetate results in a decrease in gonadotrophin and sex steroid levels. In men, serum testosterone levels, initially raised in response to early luteinising hormone (LH) release, fall to castrate levels in about 2-4 weeks.
Leuprorelin acetate is inactive when given orally.
In children: 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: Suppression of basal and stimulated gonadotropin levels to pre-pubertal levels; Suppression of prematurely increased sexual hormone levels to pre-pubertal levels and arrest of premature menstruation; Arrest/involution of somatic pubertal development (Tanner stages); Improvement/normalisation of the ratio of chronological age to bone age; Prevention of progressive bone age acceleration; Decrease of growth velocity and its normalization; Increase in final height.
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 15 mg 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.
30 mg: Leuprorelin acetate, the active ingredient in ENANTONE L.P. 30 mg, is a synthetic analogue of the naturally occurring hypothalamic releasing factor, LHRH, which works to control the release of the gonadotropic hormones LH (luteinizing hormone) and FSH (follicle-stimulating hormone) from the anterior lobe of the pituitary gland. These hormones stimulate the gonadal steroid synthesis.
In contrast to the physiological LHRH released from the hypothalamus in a pulsatile mode, leuprorelin acetate, also known as an LHRH agonist, works to block the LHRH receptors of the pituitary gland with chronic therapeutic use, and after an initial short-term stimulatory effect, causes them to become "desensitized" ("down-regulated").
As a consequence, reversible pituitary suppression of gonadotropin release occurs, followed by a decrease in testosterone levels, thereby influencing the growth of prostate cancer, which is normally stimulated by dihydrotestosterone (DHT) formed by reduction of testosterone in the prostate cells.
Chronic administration of leuprorelin acetate leads to a decrease in the number and/or sensitivity ("down-regulation") of the LHRH receptors present in the pituitary gland, resulting in a decrease in LH, FSH, and DHT levels, thereby reducing the testosterone level to the castration range.
The hormone-decreasing and inhibitory effect of leuprorelin acetate on the growth of prostate cancer has also been demonstrated in animal studies.
Experimental and clinical studies demonstrated that 6-monthly treatment with ENANTONE L.P. 30 mg results in the inhibition of gonadotropin release after an initial stimulatory effect.
In the man the subcutaneous administration of ENANTONE L.P. 30 mg causes an initial short-term rise in LH and FSH, accompanied by a transient increase in testosterone and DHT levels. As a short term exacerbation of symptoms has been reported in the first few weeks of treatment in isolated cases, the administration of an appropriate anti-androgen should be considered in patients with prostate cancer.
Long-term administration of ENANTONE L.P. 30 mg leads to a decrease in LH and FSH levels in all patients, thereby resulting in a decrease in androgen in these patients to levels comparable to those seen after bilateral orchiectomy. These changes usually occur two to three weeks after commencement of therapy, and are maintained during the entire course of treatment. If appropriate, a treatment with ENANTONE L.P. 30 mg, which has to be administered every six months, represents a viable alternative to orchiectomy. To date, the maintenance of suppressed testosterone levels in the castration range with continuous administration of leuprorelin acetate has been confirmed for five years.
Clinical Studies: 3.75 mg/11.25 mg: Prostate cancer: A randomised, open-label, comparative multi-centre study was performed to compare the efficacy and safety of the 3.75 mg and 11.25 mg depots of leuprorelin. 48% of patients included had locally advanced disease (T3N0M0), 52% of patients had metastatic disease. 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.
In an open, prospective clinical trial involving 205 patients receiving 3.75 mg leuprorelin on a monthly basis as treatment for metastatic prostate cancer, the long-term efficacy and safety of leuprorelin was assessed. 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 in combination with anti-androgens (this difference relating to baseline differences between groups).
In a meta-analysis involving primarily patients with metastatic disease, no statistically significant difference in survival was found for patients treated with GnRH analogues compared with patients treated with orchidectomy.
In another randomised, open-label, multi-centre comparative trial, in prostate cancer patients leuprorelin in combination with flutamide has been shown to significantly improve disease-free survival and overall survival when used as an adjuvant therapy to radiotherapy in 88 patients with high-risk localised (T1-T2 and PSA of at least 10 ng/mL or a Gleason score of at least 7), or locally advanced (T3-T4) prostate cancer. The optimum duration of adjuvant therapy has not been established. This US study used a higher dose of leuprorelin (7.5 mg/month) which is therapeutically equivalent to the European licensed dose.
The use of a GnRH agonist may be considered after prostatectomy in selected patients considered at high risk of disease progression. There are no disease-free survival data or survival data with leuprorelin in this setting.
11.25 mg: Premenopausal breast cancer: The following table shows the antitumor effect (the effectiveness rate) and the inhibition rate of serum estradiol concentration at the menopausal level observed in a clinical study in which 11.25 mg as Leuprorelin Acetate was subcutaneously administered to premenopausal breast cancer patients once every 12 weeks (concomitantly with tamoxifen citrate 20 mg/day). (See Table 1.)

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The recurrence-free survival rate in the clinical studies in which 11.25 mg as Leuprorelin Acetate was administered up to 96 weeks to 70 of the previously mentioned patients in status of post (premenopausal breast cancer) surgery was 93.5% (two-sided 95% confidence interval: 87.23 to 99.74%).
In a randomized controlled, non-inferiority design study conducted in Germany and the Ukraine in which Leuprorelin Acetate 11.25 mg at 3-month intervals or cyclophosphamide, methotrexate, fluorouracil (CMF) therapy was given to pre- and peri-menopausal women with breast cancer (T1-3, N+M0), positive estrogen receptor status (ER+) and curative approach of surgery within six weeks prior to enrolment progression-free survival rates were shown as follows. (See Table 2.)

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Pharmacokinetics: 3.75 mg: Studies show that single intramuscular or subcutaneous doses of leuprorelin acetate over the dose range 3.75 to 15 mg results in detectable levels of leuprorelin acetate for more than 28 days, good bioavailability, a consistent and predictable pharmacokinetic profile, and biological efficacy at plasma levels of less than 0.5 ng/ml. The pharmacokinetic profile is similar to that seen in animal studies using the compound, with an initial high level of drug released from the microcapsules during reconstitution and injection followed by a plateau over a 2-3 week period before levels gradually become undetectable. There appears to be no significant difference between the routes of administration (im vs sc) in biological effectiveness or pharmacokinetics.
The metabolism, distribution and excretion of leuprorelin acetate in humans have not been fully determined.
Children with Central Precocious Puberty (CPP): Following a single subcutaneous administration of leuprorelin acetate 1 month depot at a dosage of 30 mcg/kg body-weight, peak serum levels of 7.81 ± 3.59 ng/mL were attained at about 1 hour after administration. Serum levels declined rapidly to 0.15 ± 0.06 ng/mL by day 1 after administration and remained below 0.07 ng/mL from day 3 for 4 weeks (Figure 1). The AUC 0-672 was 105.78 ± 52.40 ng.hr/mL. (See Figure 1.)

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11.25 mg: Leuprorelin acetate is well absorbed after subcutaneous injection. It binds to the luteinising hormone-releasing hormone (LHRH) receptors and is rapidly degraded. An initially high plasma level of leuprorelin acetate peaks at around 3 hours after Enantone L.P. 11.25 mg injection, followed by a decrease to maintenance levels in 7 to 14 days. Enantone L.P. 11.25 mg 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.
In children: Figure 2 presents 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).
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). (See Figure 2.)

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Premenopausal breast cancer: When 11.25 mg, as leuprorelin acetate, was administered subcutaneously to patients (in status of post surgery) with premenopausal breast cancer two times at 12-week intervals (concomitantly with tamoxifen citrate 20 mg/day), the blood concentration (the unchanged compound and its metabolite M-I) was as shown as follows. The blood concentrations of leuprorelin including its metabolite M1 attained steady state at week 16 after administration, and remained at approximately 0.2 ng/mL up to week 24. (See Figure 3.)

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30 mg: The active ingredient leuprorelin acetate is continuously released from the lactic acid polymer for a period of 6 months after injection of the ENANTONE L.P. 30 mg depot suspension. The carrier polymer is absorbed over time in a similar fashion to surgical suture material.
After single s.c. injection of ENANTONE L.P. 30 mg serum levels of leuprorelin rise quickly with a subsequent decrease to a plateau within a few days. Within two hours mean maximum serum levels of 102 ng/ml are measured. In the plateau phase detectable serum levels were found until up to >26 weeks after administration. In some patients, leuprorelin levels have been observed for up to 30 weeks. Fig. 4 shows the course of leuprorelin levels after a single administration of ENANTONE L.P. 30 mg.
An initial re-increase of testosterone levels was observed in median after approx. 200 days in case no subsequent injection was administered. (See Figure 4.)

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The distribution volume of leuprorelin is 36 l in men; total clearance is 139.6 ml/min (measured under treatment with Enantone Monthly Depot).
With repeated administration, a persistent suppression of testosterone levels to the castration range occurs, without the testosterone levels undergoing a transient rise, as after the first injection.
In patients with impaired renal function, higher leuprorelin serum levels were measured in some cases whereas in patients with hepatic dysfunction lower values were found. However, this observation appears to be of no clinical relevance.
Toxicology: Preclinical safety data: 3.75 mg/11.25 mg: Animal studies have shown that leuprorelin acetate 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 GnRH agonist.
30 mg: Preclinical studies with leuprorelin acetate show impact on the reproductive system in both sexes, which are expected as a result of the known pharmacological effect. These effects are in principle reversible after a recovery phase (see Pharmacodynamics as previously mentioned).
Leuprorelin acetate shows no teratogenic effect. Due to the pharmacological effect on the reproductive system embryotoxicity and - lethality appeared in rabbits.
Carcinogenicity studies have been performed in rats and mice over 24 months. After subcutaneous injection a dose-dependent increase in pituitary adenomas at dosages of 0.6 mg to 4 mg/kg/day was observed in rats. No such effect was observed in mice, so that the effect in rats can be considered as species-specific.
Leuprorelin acetate had no mutagenic effect in a series of in vitro and in vivo studies.