Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, emergency contraceptives . ATC code. G03AD02.

Ulipristal acetate is an orally-active synthetic selective progesterone receptor modulator which acts via high-affinity binding to the human progesterone receptor. When used for emergency contraception the mechanism of action is inhibition or delay of ovulation via suppression of the luteinising hormone (LH) surge. Pharmacodynamic data show that even when taken immediately before ovulation is scheduled to occur (when LH has already started to rise), ulipristal acetate is able to postpone follicular rupture for at least 5 days in 78.6% of cases (p<0.005 vs. levonorgestrel and vs. placebo) (see Table).



Prevention of ovulation1,§
Placebo       Levonorgestrel                  Ulipristal acetate n=50               n=48                            n=34
Treatment before LH                    n=16               n=12                             n=8 surge                                  0.0%              25.0%                       100% p<0.005* 
Treatment after LH surge                n=10                  n=14                        n=14 but before LH peak                     10.0%                 14.3%                   78.6% p<0.005* NS†
Treatment after LH peak                 n=24                  n=22                         n=12 4.2%                  9.1%                         8.3%
NS†                          NS*
1: Brache et al, Contraception 2013
§: defined as presence of unruptured dominant follicle five days after late follicular-phase treatment *: compared to levonorgestrel
NS: non statistically significant
†: compared to placebo

Ulipristal acetate also has high affinity for the glucocorticoid receptor and in vivo, in animals, antiglucocorticoid effects have been observed. However, in humans, no such effect has been observed even after repeat administration at the daily dose of 10 mg. It has minimal affinity to the androgen receptor and no affinity for the human estrogen or mineralocorticoid receptors.

Results from two independent randomized controlled trials (see Table) showed the efficacy of ulipristal acetate to be non-inferior to that of levonorgestrel in women who presented for emergency contraception between 0 and 72 hours after unprotected intercourse or contraceptive failure. When the data from the two trials were combined via meta-analysis, the risk of pregnancy with ulipristal acetate was significantly reduced compared to levonorgestrel (p=0.046).

Pregnancy rate (%)                       Odds ratio [95% CI] of pregnancy Randomized          within 72h of unprotected intercourse or contraceptive         risk, ulipristal acetate vs controlled trial                            failure2                                     levonorgestrel2 Ulipristal acetate            Levonorgestrel
HRA2914-507                    0.91                        1.68                          0.50 [0.18-1.24] (7/773)                    (13/773)
HRA2914-513                    1.78                        2.59                          0.68 [0.35-1.31] (15/844)                    (22/852)
Meta-analysis                  1.36                        2.15                          0.58 [0.33-0.99] (22/1617)                   ( 35/1625)
2 – Glasier et al, Lancet 2010

Two trials provide efficacy data on Ella used up to 120 hours after unprotected intercourse. In an open-label clinical trial, which enrolled women who presented for emergency contraception and were treated with ulipristal acetate between 48 and 120 hours after unprotected intercourse, a pregnancy rate of 2.1% (26/1241) was observed. In addition, the second comparative trial described above also provides data on 100 women treated with ulipristal acetate from 72 to 120 hours after unprotected intercourse, in whom no pregnancies were observed.

Limited and inconclusive data from clinical trials suggest a possible trend for a reduced contraceptive efficacy of ulipristal acetate with high body weight or BMI (see section 4.4). The meta-analysis of the four clinical studies conducted with ulipristral acetate presented below excluded women who had further acts of unprotected intercourse.


Underweight      Normal           Overweight       Obese
BMI (kg/m2)
0 - 18.5         18.5-25          25-30            30-
N total              128              1866             699              467 N pregnancies        0                23               9                12 Pregnancy rate       0.00%            1.23%            1.29%            2.57% Confidence
0.00 – 2.84      0.78 – 1.84      0.59 – 2.43      1.34 - 4.45 interval

A post-marketing observational study evaluating efficacy and safety of Ella in adolescents aged 17 and younger showed no difference in the safety and efficacy profile compared to adult women aged 18 and older.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Following oral administration of a single 30 mg dose, ulipristal acetate is rapidly absorbed, with a peak plasma concentration of 176 ± 89 ng/ml occurring approximately 1 hour (0.5-2.0 h) after ingestion, and with an AUC0-∞ of 556 ± 260 ng.h/ml.

Administration of ulipristal acetate together with a high-fat breakfast resulted in approximately 45% lower mean Cmax, a delayed Tmax (from a median of 0.75 hours to 3 hours) and 25% higher mean AUC0-∞ compared with administration in the fasted state. Similar results were obtained for the active mono-demethylated metabolite.

Distribution

Ulipristal acetate is highly bound (>98%) to plasma proteins, including albumin, alpha-l-acid glycoprotein, and high density lipoprotein.

Ulipristal acetate is a lipophilic compound and is distributed in breast milk, with a mean daily excretion of 13.35 µg [0-24 hours], 2.16 µg [24-48 hours], 1.06 µg [48-72 hours], 0.58 µg [72-96 hours], and 0.31 µg [96-120 hours].

In vitro data indicate that ulipristal acetate may be an inhibitor of BCRP (Breast Cancer Resistance Protein) transporters at the intestinal level. The effects of ulipristal acetate on BCRP are unlikely to have any clinical consequences.

Ulipristal acetate is not a substrate for either OATP1B1 or OATP1B3.

Biotransformation /elimination
Ulipristal acetate is extensively metabolized to mono-demethylated, di-demethylated and hydroxylated metabolites. The mono-demethylated metabolite is pharmacologically active. In vitro data indicate that this is predominantly mediated by CYP3A4, and to a small extent by CYP1A2 and CYP2A6. The terminal half-life of ulipristal acetate in plasma following a single 30 mg dose is estimated to 32.4 ± 6.3 hours, with a mean oral clearance (CL/F) of 76.8 ± 64.0 L/h.

Special populations

No pharmacokinetic studies with ulipristal acetate have been performed in females with impaired renal or hepatic function.