Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Other sex hormones and modulators of the genital system, ATC code: G03XX01.

Mechanism of action
Intrarosa contains the active substance prasterone, i.e. dehydroepiandrosterone (DHEA), which is biochemically and biologically identical to the endogenous human DHEA, a precursor steroid which is inactive by itself and it is converted into oestrogens and androgens. Intrarosa is thus different from the oestrogens preparations since it delivers also androgen metabolites.

An oestrogen-mediated increase in the number of superficial and intermediate cells and decrease in the number of parabasal cells in the vaginal mucosa is noted. In addition, the vaginal pH decreased towards the normal range, thus facilitating the growth of the normal bacterial flora.

Clinical efficacy

Physiological responses (objective measures)
Efficacy data were obtained from two US and Canadian randomised, double-blind, placebo-controlled, multicentre, pivotal phase III studies (ERC-231/Study 1 and ERC-238/Study 2) performed in postmenopausal women aged 40 to 80 years (mean age = 58.6 years in Study 1 and 59.5 years in Study 2) with vulvar and vaginal atrophy (VVA). At baseline, women had ≤ 5.0% superficial cells in the vaginal smear, a vaginal pH ˃ 5.0 and they had identified dyspareunia (moderate to severe) as their most bothersome symptom (MBS) of VVA. After 12 weeks of daily treatment with a prasterone 6.5 mg pessary (n=81 in Study 1 and n=325 in Study 2), the change from baseline, in comparison with placebo treatment (n=77 in Study 1 and n=157 in Study 2), demonstrated significant improvements of the 3 co-primary endpoints compared to placebo in both studies, namely increase of the percentage of superficial cells (p<0.0001), decrease of the percentage of parabasal cells (p<0.0001), and decrease in the vaginal pH (p<0.0001).

Symptoms (subjective measures)
The MBS dyspareunia (co-primary endpoint) was assessed at baseline and 12 weeks with the severity scored as follows: None=0, Mild=1, Moderate=2, Severe=3.
Table 2 shows the mean change in severity score in MBS dyspareunia after 12 weeks with associated statistical testing for the difference vs. placebo for Study 1 (ERC-231) and Study 2 (ERC-238).



Table 2: Primary efficacy analysis – Change from baseline to week 12 in the most bothersome symptom dyspareunia (ITT population; LOCF)

Study                                                      Dyspareunia Intrarosa 6.5 mg                  Placebo                    p-value
Study 1                         -1.27                          -0.87                     0.0132 Study 2                         -1.42                          -1.06                     0.0002 
Table 3 shows the percentage of subjects who reported a change from baseline in their MBS dyspareunia at week 12. “Improvement” was defined as a reduction in the severity score of 1 or more.
“Relief” was defined as no or only mild symptoms at week 12. “Substantial improvement” was restricted to patients who had moderate or severe MBS at baseline and changed from severe to mild or severe or moderate to none.

Table 3: Percentage of patients with improvement, relief or substantial improvement of MBS dyspareunia after 12 weeks on Intrarosa vs. placebo (ITT, LOCF)

Substantial
Improvement                     Relief improvement
Intrarosa      Placebo      Intrarosa     Placebo   Intrarosa      Placebo Study 1                72.8%         58.4%         58.0%          44.2%      43.2%       29.9% (Intrarosa: n= 81)        (p=0.0565)                  (p=0.0813)              (p=0.0821) (Placebo: n= 77)
Study 2               80.3%         65.0%         68.6%          51.6%      47.1%       35.7% (Intrarosa: n= 325)       (p=0.0003)                  (p=0.0003)              (p=0.0179) (Placebo: n= 157)

Clinical safety
Apart from the main two 12-week phase III clinical studies, the safety data of Intrarosa has also been obtained from one non comparative open-label safety study of one year.

Cases of breast and ovarian cancer have been reported in women treated with 6.5 mg of prasterone for 52 weeks (see section 4.4).

Cases of abnormal Pap smears either ASCUS or LSIL have been reported with a common frequency in women treated with Intrarosa for 52 weeks (see section 4.4).

Endometrial safety
On the 389 evaluable end-of-study endometrial biopsies performed after 52 weeks of treatment with Intrarosa, no histological abnormalities were reported on the biopsies.

Paediatric population
Intrarosa is not indicated for children. See section 4.2 for additional information.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
Absorption
Prasterone administered in the vagina is an inactive precursor that enters the vaginal cells and is converted intracellularly into cell-specific small amounts of both oestrogens and androgens depending upon the level of enzymes expressed in each cell type. The beneficial effects on the symptoms and signs of vulvar and vaginal atrophy are exerted through activation of the vaginal oestrogen and androgen receptors.
In a study conducted in postmenopausal women, administration of the Intrarosa pessary once daily for 7 days resulted in a mean prasterone Cmax and area under the curve from 0 to 24 hours (AUC0-24) at day 7 of 4.4 ng/mL and 56.2 ng h/mL, respectively, which were significantly higher than those in the group treated with placebo (Table 4; Figure 1). The Cmax and AUC0-24 of the metabolites testosterone and estradiol were also slightly higher in women treated with the Intrarosa pessary compared to those receiving placebo but all remained within normal values of postmenopausal women (< 10 pg estradiol/mL; < 0.26 ng testosterone/mL) as measured by validated mass spectrometry-based assays for both the study samples and reference values.

Table 4: Cmax and AUC0-24 of prasterone, testosterone, and estradiol on Day 7 following daily administration of placebo or Intrarosa (mean ± S.D.)

Placebo (N=9)           Intrarosa (N=10)
Cmax (ng/mL)          1.60 (±0.95)              4.42 (±1.49)
Prasterone
AUC0-24 (ngh/mL)         24.82 (±14.31)           56.17 (±28.27) Cmax (ng/mL)         0.12 (±0.04)1              0.15 (±0.05)
Testosterone
AUC0-24 (ngh/mL)          2.58 (±0.94)1              2.79 (±0.94) Cmax (pg/mL)          3.33 (±1.31)              5.04 (±2.68)
Estradiol
AUC0-24 (pgh/mL)         66.49 (±20.70)           96.93 (±52.06) 1
: N=8



Figure 1: Serum concentrations of prasterone (A), testosterone (B), and estradiol (C) measured over a 24h period on day 7 following daily administration of placebo or Intrarosa (mean ± S.D.) 
Distribution
The distribution of intravaginal (exogenous) prasterone is mainly local but some increase in systemic exposure is observed especially for the metabolites but within normal values.

Biotransformation
Exogenous prasterone is metabolized in the same manner as endogenous prasterone. Systemic metabolism has not been studied in this application.
Elimination
Systemic elimination has not been studied specifically for this application.