Ulipristal

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 ovulation^1,§:

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.

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 AU_C0-∞ of 556 ± 260 ng.h/ml.

Administration of ulipristal acetate together with a high-fat breakfast resulted in approximately 45% lower mean C_max, a delayed T_max (from a median of 0.75 hours to 3 hours) and 25% higher mean AUC_0-∞ 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 metabolised 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.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity. Most findings in general toxicity studies were related to its mechanism of action as a modulator of progesterone and glucocorticoid receptors, with antiprogesterone activity observed at exposures similar to therapeutic levels.

Information from reproductive toxicity studies is limited due to the absence of exposure measurement in these studies. Ulipristal acetate has an embryolethal effect in rats, rabbits (at repeated doses above 1 mg/kg) and in monkeys. At these repeated doses, the safety for a human embryo is unknown. At doses which were low enough to maintain gestation in the animal species, no teratogenic effects were observed.

Carcinogenicity studies (in rats and mice) showed that ulipristal acetate is not carcinogenic.