CLINICAL PHARMACOLOGY
Mechanism of Action
When taken immediately before ovulation is to occur, ella postpones follicular rupture. The likely primary mechanism of action of ulipristal acetate for emergency contraception is therefore inhibition or delay of ovulation; however, alterations to the endometrium that may affect implantation may also contribute to efficacy.
Pharmacodynamics
Ulipristal acetate is a selective progesterone receptor modulator with antagonistic and partial agonistic effects (a progesterone agonist/antagonist) at the progesterone receptor. It binds the human progesterone receptor and prevents progesterone from occupying its receptor.
The pharmacodynamics of ulipristal acetate depends on the timing of administration in the menstrual cycle. Administration in the mid-follicular phase causes inhibition of folliculogenesis and reduction of estradiol concentration. Administration at the time of the luteinizing hormone peak delays follicular rupture by 5 to 9 days. Dosing in the early luteal phase does not significantly delay endometrial maturation but decreases endometrial thickness by 0.6 ± 2.2 mm (mean ± SD).
Pharmacokinetics
Absorption
Following a single dose administration of ella in 20 women under fasting conditions, maximum plasma concentrations of ulipristal acetate and the active metabolite, monodemethyl-ulipristal acetate, were 176 and 69 ng/ml and were reached at 0.9 and 1 hour, respectively.
Figure 1: Mean (± SD) Plasma Concentration-time Profile of Ulipristal Acetate and Monodemethyl-ulipristal Acetate Following Single Dose Administration of 30 mg Ulipristal Acetate
Table 2: Pharmacokinetic Parameter Values Following Administration of ella (ulipristal acetate) Tablet 30 mg to 20 Healthy Female Volunteers under Fasting Conditions
|
Mean (± SD)
|
Cmax
(ng/ml)
|
AUC0-t
(ng•hr/ml)
|
AUC0-∞
(ng•hr/ml)
|
tmax
(hr)*
|
t1/2
(hr)
|
Ulipristal acetate
|
176 (89)
|
548 (259)
|
556 (260)
|
0.9 (0.5-2.0)
|
32 (6.3)
|
Monodemethyl-ulipristal acetate
|
69 (26)
|
240 (59)
|
246 (59)
|
1.00 (0.8-2.0)
|
27 (6.9)
|
Cmax = maximum concentration AUC0-t = area under the drug concentration curve from time 0 to time of last determinable concentration AUC0-∞ = area under the drug concentration curve from time 0 to infinity tmax = time to maximum concentration t1/2 = elimination half-life * Median (range)
Effect of food: Administration of ella together with a high-fat breakfast resulted in approximately 40-45% lower mean Cmax, a delayed tmax (from a median of 0.75 hours to 3 hours) and 20-25% higher mean AUC0-∞ of ulipristal acetate and monodemethyl-ulipristal acetate compared with administration in the fasting state. These differences are not expected to impair the efficacy or safety of ella to a clinically significant extent; therefore, ella can be taken with or without food.
Distribution
Ulipristal acetate is highly bound (> 94%) to plasma proteins, including high density lipoprotein, alpha-l-acid glycoprotein, and albumin.
Metabolism
Ulipristal acetate is metabolized to mono-demethylated and di-demethylated metabolites. In vitro data indicate that this is predominantly mediated by CYP3A4. The mono-demethylated metabolite is pharmacologically active.
Excretion
The terminal half-life of ulipristal acetate in plasma following a single 30 mg dose is estimated to 32.4 ± 6.3 hours.
Drug interactions
CYP3A4 inducers: When a single 30 mg dose of ulipristal acetate was administered following administration of the strong CYP3A4 inducer, rifampin 600 mg once daily for 9 days, Cmax and AUC of ulipristal acetate decreased by 90% and 93% respectively. The Cmax and AUC of monodemethyl-ulipristal acetate decreased by 84% and 90% respectively [see Drug Interactions ].
CYP3A4 inhibitors: When a single 10 mg dose of ulipristal acetate was administered following administration of the strong CYP3A4 inhibitor, ketoconazole 400 mg once daily for 7 days, Cmax and AUC of ulipristal acetate increased by 2- and 5.9- fold, respectively. While the AUC of monodemethyl-ulipristal acetate increased by 2.4-fold, Cmax of monodemethyl-ulipristal acetate decreased by 47%. There was no in vivo drug-drug interaction study between ulipristal acetate 30 mg and CYP3A4 inhibitors [see Drug Interactions].
P-glycoprotein (P-gp) transporters: When a single 60 mg dose of fexofenadine, a substrate of P-gp glycoprotein, was administered 1.5 hours after the administration of a single 10 mg dose of ulipristal acetate, there was no increase in Cmax or AUC of fexofenadine.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity: Carcinogenicity studies with ulipristal acetate have not been conducted.
Genotoxicity: Ulipristal acetate was not genotoxic in the Ames assay, in vitro mammalian assays utilizing mouse lymphoma cells and human peripheral blood lymphocytes, and in an in vivo micronucleus assay in mice.
Impairment of Fertility: Single oral doses of ulipristal acetate prevented ovulation in 50% of rats at 2 times the human exposure based on body surface area (mg/m2). Single doses of ulipristal acetate given on post-coital days 4 or 5 prevented pregnancy in 80 - 100% of rats and in 50% of rabbits when given on post-coital days 5 or 6 at drug exposures 4 and 12 times the human exposure based on body surface area. Lower doses administered for 4 days to rats and rabbits were also effective at preventing ovulation and pregnancy.
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