Estetrol demonstrates anti-gonadotropic activity characterised by a dose-dependent decrease in both serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels.
The progestogen drospirenone possesses progestagenic, antigonadotropic, antiandrogenic and mild antimineralocorticoid properties and has no oestrogenic, glucocorticoid or antiglucocorticoid activity. These properties are pharmacologically similar to the natural hormone progesterone.
The contraceptive effect of drospirenone/estetrol is based on the interaction of various factors, the most important of which is inhibition of ovulation.
Estetrol is rapidly absorbed after ingestion. After intake of drospirenone/estetrol, average peak plasma concentrations of 17.9 ng/mL are reached 0.5-2 hours after single ingestion.
The overall exposure to estetrol is similar irrespective of food intake. The Cmax of estetrol is reduced with approximately 50% after food intake.
Estetrol does not bind to SHBG. Estetrol displayed moderate binding to human plasma proteins (45.5% to 50.4%) and human serum albumin (58.6%), and low binding to human alpha-glycoprotein (11.2%). Estetrol is equally distributed between red blood cells and plasma.
In vitro studies indicated that estetrol is a substrate of P-gp and BCRP transporters. Co-administration of drugs that affect the activity of P-gp and BCRP is however unlikely to result in a clinically relevant drug interaction with estetrol.
After oral administration, estetrol undergoes extensive phase 2 metabolism to form glucuronide and sulphate conjugates. The two main metabolites estetrol-3-glucuronide and estetrol-16-glucuronide have negligible oestrogenic activity. UGT2B7 is the dominant UGT isoform involved in the biotransformation of estetrol into a direct glucuronide. Estetrol undergoes sulfation, mainly by specific oestrogen sulfotransferase (SULT1E1).
The terminal elimination half-life (t1/2) of estetrol was observed to be around 24 hours under steady state conditions.
Following administration of a single oral solution of 15 mg [14C]-estetrol, approximately 69% of the total recovered radioactivity was detected in urine and 21.9% in faeces.
When drospirenone/estetrol combination is administered from 1 to 5 times the dose, estetrol plasma levels do not show any relevant deviation from dose-proportionality, after single administration as well as in steady-state conditions.
Steady-state is achieved after 5 days. Cmax of estetrol is about 17.9 ng/mL and is reached 0.5-2 hours after dosing. Average serum concentrations are 2.46 ng/mL. The accumulation is very limited with daily area under the curve (AUC) at steady-state 60% larger than after a single dose.
Drospirenone is rapidly and almost completely absorbed. After intake of drospirenone/estetrol, Cmax of about 48.7 ng/mL is reached at about 1-3 h after multiple ingestion. Bioavailability is between 76 and 85%. The overall exposure to drospirenone is similar regardless of food intake around tablet intake of drospirenone/estetrol.
Drospirenone is bound to serum albumin and does not bind to SHBG or CBG. Only 3-5% of the total serum concentrations of the active substance are present as free steroid. The mean apparent volume of distribution of drospirenone is 3.7 ± 1.2 L/kg.
Drospirenone is extensively metabolised after oral administration. The major metabolites in plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, formed by reduction and subsequent sulfation. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4.
After oral administration of drospirenone/estetrol, serum drospirenone levels decrease with a terminal elimination half-life observed around 34 hours. The metabolic clearance rate of drospirenone in serum is 1.5 ± 0.2 mL/min/kg. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the faeces and urine at an excretion ratio of about 1.2 to 1.4. The t1/2 of metabolite excretion with the urine and faeces is about 40 h.
Drospirenone plasma levels do not show any relevant deviation from dose-proportionality over the 3-15 mg dose range, after single administration as well as in steady-state conditions.
Steady-state is achieved after 10 days. Cmax of drospirenone of about 48.7 ng/mL is reached after about 1-3 hours after dosing. The mean concentration during steady state over a 24-hour dosing period is approximately 22 ng/mL. The accumulation is very limited with daily AUC at steady-state 80% larger than after a single dose.
No studies were performed to evaluate the effect of renal disease on the pharmacokinetics of estetrol. In a study performed with drospirenone 3 mg alone administered orally for 14 days, steady-state serum drospirenone levels in women with mild renal impairment (creatinine clearance (CLcr)=50-80 mL/min) were comparable to those of women with normal renal function. The serum drospirenone levels were on average 37% higher in women with moderate renal impairment (CLcr=30-50 mL/min) compared with those in women with normal renal function.
No studies were conducted to evaluate the effect of hepatic disease on the pharmacokinetics of estetrol. In a single dose study, oral clearance of drospirenone (CL/F) was decreased approximately 50% in volunteers with moderate hepatic impairment as compared to those with normal liver function.
The pharmacokinetics of estetrol and drospirenone in postmenarcheal female adolescents (below 16 years of age) after intake of drospirenone/estetrol have not been investigated.
No clinically relevant differences in the pharmacokinetics of estetrol or drospirenone between Japanese and Caucasian women have been observed after single dose administration of drospirenone/estetrol.
Repeated dose toxicity studies with estetrol, drospirenone or the combination have indicated expected estrogenic and gestagen effects.
At exposures exceeding those in users of drospirenone/estetrol (~27-fold multiple for estetrol and ~3.5-fold multiple for drospirenone), ventricular histological changes, without clinical effects, were observed in monkeys after repeated administration of the combination.
Reproductive toxicity studies in rats and rabbits performed with estetrol have shown embryotoxic and fetotoxic effects in animals at clinically relevant exposures; the effects possibly dependent on uterotonic effects in late gestation.
Genotoxicity and carcinogenicity studies were not conducted with the combination. Estetrol and drospirenone are not considered to be genotoxic. However, it is known that due to their hormonal action, sex steroids can promote the growth of certain hormone-dependent tissues and tumours.
Environmental risk assessment studies with drospirenone have shown that drospirenone may pose a risk to the aquatic environment (see section 6.6). Environmental risk assessment studies with estetrol including the Japanese medaka fish extended one generation reproduction test indicated that the predicted environmental exposure to estetrol will not affect the aquatic ecosystem.
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