Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties
Pharmacotherapeutic group: gonadotropin releasing hormone analogues.
ATC code: L02AE04
Mechanism of action and pharmacodynamic effects
Triptorelin, the active substance in Decapeptyl depot, is a GnRH agonist with a similar structure to natural GnRH (Gonadorelin). Triptorelin is different from the endogenous hormone by amino acid glycine in the 6-position has been replaced by D-tryptophan. This change of the GnRH molecule results in greater and more long-lasting effect from the release of LH and FSH from the pituitary gland than natural GnRH.

Initially, triptorelin causes a transient increase in LH and FSH release, with accompanying elevated testosterone, oestrogen and progesterone levels in plasma. The gonadotropin release is then 
suppressed, which leads to testosterone or oestrogen in the plasma falling to castration prepubertal or postmenopausal values after 2-4 weeks.

Subsequent injections of Decapeptyl depot do not cause any initial stimulation of the pituitary and gonads. The effects of triptorelin are reversible.

In treated women, menstruation returns 2-3 months after the last injection of Decapeptyl depot.


Clinical efficacy and safety

Prostate cancer
Following an intramuscular injection of Decapeptyl depot 3.75 mg in healthy male volunteers, the serum testosterone levels did not increase to the maximum level until day 4 before then falling to low levels by 4 weeks. After week 8, the levels had increased once more. A similar change in testosterone levels was observed in patients with advanced prostate cancer who received intramuscular injections of triptorelin embonate. After the second injection, the testosterone levels remained within the castration limit.

Breast cancer
Clinical studies performed in pre-menopausal women with hormone receptor-positive early-stage breast cancer have been conducted with triptorelin in order to suppress oestradiol ovarian secretion, the main source of oestrogens. Based on studies performed in healthy women and women with endometriosis, the effect of triptorelin is achieved 3-4 weeks after administration.
Two phase 3 studies (SOFT and TEXT) have explored the 5-year benefit of ovarian function suppression (OFS) in combination with tamoxifen (T) or an aromatase inhibitor (exemestane - E) in pre-menopausal women with hormone receptor-positive early-stage breast cancer.
Triptorelin was the main treatment used to achieve OFS (91.0% of randomized subjects in the SOFT study, and 100% in the TEXT study). The remaining 9% of women in the SOFT study had bilateral oophorectomy or bilateral ovarian irradiation.
The SOFT study included subjects following breast surgery who remained pre-menopausal after the completion of adjuvant or neoadjuvant chemotherapy and pre-menopausal women who had not received chemotherapy and for whom adjuvant T alone was considered suitable treatment. Subjects were randomized to receive E+OFS, T+OFS or T alone. In the TEXT study women were included following breast surgery and randomized to treatment with T+OFS or E+OFS; those receiving chemotherapy commenced it concurrently with the GnRH analogue after randomization. Efficacy in both studies was measured using the primary endpoint of 5-year disease-free survival (DFS) and secondary endpoints included breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI) and overall survival (OS).

SOFT study results
The SOFT study was designed to answer the question of the added value of OFS to tamoxifen as adjuvant treatment of pre-menopausal women with hormone receptor-positive early stage breast cancer.
This OFS question analysis compared DFS between subjects randomly assigned to T+OFS versus T alone. At a median follow-up of 67 months (5.6 years), DFS events were reported for 299/2033 subjects (14.7%) in the intention-to-treat population (ITT).
Overall, 53.3% of subjects received prior chemotherapy (i.e. subjects who tended to have a high risk of recurrence of breast cancer). The absolute difference at 5 years was more notable among subjects who received prior chemotherapy: DFS, 80.7% (T+OFS) versus 77.1% (T alone) (Table 1).


Table 1 OFS Question: 67-month Efficacy Results for Subjects who Received Prior Chemotherapy (ITT Population)
Efficacy Endpoints T Alone                     T+OFS                       T Alone vs T+OFS N=542                      N=542                       Hazard Ratio
Events      Event-free     Events        Event-free    (95% CI) rates (%)                    rates (%)
DFS[a]              122         77.1           107           80.7          0.82 (0.64 to 1.07) BCFI                116         78.0           97            82.5          0.78 (0.60 to 1.02) DRFI                90          83.6           82            84.8          0.87 (0.64 to 1.17) OS[b]               57          90.9           39            94.5          0.64 (0.42 to 0.96) BCFI=breast cancer-free interval, CI=confidence interval, DFS=disease-free survival, DRFI=distant recurrence-free interval, ITT=intention-to-treat, OFS=ovarian function suppression, OS=overall survival, T=tamoxifen a Disease-free survival is defined as the first occurrence of local or distant recurrence, contralateral breast cancer, or death from any cause b Overall survival data immature at 67-months.

Combined SOFT and TEXT study results
The TEXT study was designed to evaluate the role of aromatase inhibitors (AIs) (exemestane) in the adjuvant treatment of pre-menopausal women with hormone receptor-positive early stage breast cancer who are treated with OFS. The AI Question analysis combined the TEXT and SOFT studies and compared DFS between subjects randomly assigned to E+OFS versus T+OFS.

At a median follow-up of 68 months (5.7 years), DFS events were reported for 514/4690 subjects (11.0%) in the ITT population. Overall, the estimated 5-year DFS was improved at 91.1% (95% CI, 89.7% to 92.3%) among subjects assigned E+OFS versus 87.3% (95% CI, 85.7% to 88.7%) among subjects assigned T+OFS (HR=0.717; 95% CI, 0.602 to 0.855; p=0.0002). Table 2 shows the efficacy results for subjects who received prior chemotherapy in the AI analysis.
Table 2 AI Question: 68-month Efficacy Results for Subjects who Received Prior Chemotherapy (ITT Population)
Efficacy Endpoints E+OFS                        T+OFS                        Hazard Ratio N=544                      N=543                        E+OFS vs T+OFS Events      Event-free     Events        Event-free     (95% CI) rates (%)                    rates (%)
DFS[a]               81          84.3           98            80.6           0.838 (0.625 to 1.125) BCFI                 72          86.1           90            82.2           0.818 (0.600 to 1.116) DRFI                 61          88.0           77            84.6           0.808 (0.577 to 1.131) OS[b]                46          91.8           35            94.1           1.387 (0.894 to 2.154) AI=aromatase inhibitor, BCFI=breast cancer-free interval, CI=confidence interval, DFS=disease-free survival, E=exemestane, DRFI=distant recurrence-free interval, ITT=intention-to-treat, OFS=ovarian function suppression, OS=overall survival, T=tamoxifen a Disease-free survival is defined as the first occurrence of local or distant recurrence, contralateral breast cancer, or death from any cause.
b Overall survival data immature at 68-months.


An updated analysis after a median follow-up of 8 years has confirmed the positive benefit/risk profile of 5-year triptorelin treatment.

Pharmacokinetic Properties

5.2.    Pharmacokinetic properties
Decapeptyl depot contains triptorelin in the form of bioabsorbablemicro particles that are suspended in a water phase, injected intramuscularly and and constitute a prolonged-release preparation with the gradual release of the active ingredient. Maximum plasma concentration is achieved within one hour after administration and falls rapidly to steady state. Therapeutic plasma concentrations well above the level required to sustain the pharmacodynamic effect are maintained throughout the dosing interval.

After one intramuscular injection of Decapeptyl depot 3.75 mg in healthy pre-menopausal women, maximum triptorelin concentrations were observed around 2 hours post-dose and the geometric mean value of Cmax was 18.5 ng/mL.
The time to oestradiol suppression was around 4.2 days (geometric mean) and the duration of E2 suppression was around 26.7 days (geometric mean). Despite fairly high global interindividual variation, oestradiol suppression for approx. 30 days was seen 5 days after intramuscular injection of Decapeptyl depot 3.75mg.