Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Gonadotropin releasing hormone analogues
ATC code: L02A E02

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). 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.

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 98% reduction in mean PSA for ELIGARD 22.5 mg.

In a phase III randomized clinical trial including 970 patients with locally advanced prostate cancer (mainly T2c-T4 with some T1c to T2b patients with pathological regional nodal disease) of whom 483 were assigned to short-term androgen suppression (6 months) in combination with radiation therapy and 487 to long-term therapy (3 years), a non-inferiority analysis compared the short-term to long- term concomitant and adjuvant hormonal treatment with GnRH agonist (triptorelin or goserelin). The 5-year overall mortality was 19.0% and 15.2%, in the short-term and long-term groups, respectively.
The observed Hazard Ratio of 1.42 with an upper one-sided 95.71% CI of 1.79 or two-sided 95.71% CI of 1.09; 1.85 (p = 0.65 for non inferiority), demonstrate that the combination of radiotherapy plus 6 months of androgen deprivation therapy provides inferior survival as compared with radiotherapy plus 3 years of androgen deprivation therapy. Overall survival at 5 years of long-term treatment and short- term treatment shows 84.8% survival and 81.0%, respectively. Overall quality of life using QLQ-C30 did not differ significantly between the two groups (P= 0.37). Results are dominated by the population of patients with locally advanced tumours.

Evidence for the indication of high-risk localized prostate cancer is based on published studies of radiotherapy combined with GnRH analogues, including leuprorelin acetate. Clinical data from five published studies were analyzed (EORTC 22863, RTOG 85-31, RTOG 92-02, RTOG 8610, and D’Amico et al., JAMA, 2004), which all demonstrate a benefit for the combination of GnRH analogue with radiotherapy. Clear differentiation of the respective study populations for the indications locally advanced prostate cancer and high-risk localized prostate cancer was not possible in the published studies.

Clinical data have shown that radiotherapy followed by 3 years of androgen deprivation therapy is preferable to radiotherapy followed by 6 months of androgen deprivation therapy.

The recommended duration of androgen deprivation therapy in medical guidelines for T3-T4 patients receiving radiotherapy is 2-3 years.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption: In patients with advanced carcinoma of the prostate, mean serum leuprorelin concentrations following the initial injection rise to 127ng/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.
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 22.5 mg.

No drug metabolism study was conducted with ELIGARD 22.5 mg.