Chemical formula: C₁₈H₂₄O₄ Molecular mass: 304.381 g/mol PubChem compound: 27125
The active ingredient, synthetic estetrol, is chemically and biologically identical to endogenous estetrol that is produced during pregnancy by the human foetal liver.
Estetrol substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms, including vasomotor symptoms (VMS).
Estetrol is rapidly absorbed after ingestion. After intake of estetrol at doses of 14.2 mg and 18.9 mg in tablet formulation, average peak plasma concentrations of 17.9 ng/mL and 17.3-20.75 ng/mL, respectively, are reached 0.47-0.63 hours after single ingestion. The extent of exposure to estetrol is similar irrespective of food intake. The maximum observed plasma concentration (Cmax) of estetrol is reduced by approximately 50% after food intake. The peak concentration of estetrol is reached sooner in fasted conditions than in fed conditions (median time of maximum observed plasma concentration (Tmax) 0.5 hours under fasted conditions compared to 1 hour under fed conditions).
Based on results of the mass balance study the bioavailability of estetrol was estimated at least 69%.
After multiple doses of estetrol 14.2 mg taken once daily for 14 days, the median Tmax,ss is approximately 0.5 hour. Steady state is achieved after 6 to 8 days. At steady state, the Cmax, the average concentration and the minimal concentration (trough level) are 16.69 ng/mL, 3.08 ng/mL and 1.42 ng/mL, respectively.
After multiple doses of estetrol 18.9 mg taken once daily for 8 days, the median Tmax,ss is approximately 0.5 hour. Steady state is achieved after 6 to 8 days. At steady state, the Cmax, the average concentration and the minimal concentration (trough level) are 19.6 ng/mL, 3.50 ng/mL and 1.59 ng/mL, respectively.
The pharmacokinetics of estetrol are characterized by a rapid distribution phase; it is distributed and probably reabsorbed by enterohepatic cycling during the first 18 hours after oral intake. The volume of distribution determined after oral administration of a single dose of 14.2 mg was high indicating that estetrol is widely distributed in tissues.
Estetrol does not bind to SHBG. Estetrol displayed moderate binding to human plasma proteins (45.5 to 50.4%). Estetrol is equally distributed between red blood cells and plasma.
In vitro studies indicated that estetrol is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (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 both after single administration and 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.
Estetrol plasma levels do not show any relevant deviation from dose-proportionality over a dose range of 4.7 mg up to 94.4 mg (single administration).
Steady-state is achieved after 6 to 8 days. After once daily repeated oral administration of estetrol 14.2 mg or 18.9 mg, the maximum plasma concentrations of estetrol are about 16.69 ng/mL and 19.60 ng/m, respectively, and are reached 0.18-2 hours after dosing. Average plasma concentrations are 3.08 ng/mL and 3.50 ng/mL, respectively. The accumulation is very limited with daily area under the curve (AUC) at steady-state 60% larger than after a single dose and no observed increase in Cmax.
A study has been performed with a single oral dose of estetrol 18.9 mg administered in female subjects with normal hepatic function, mild hepatic impairment (Child-Pugh class A), moderate hepatic impairment (Child-Pugh class B), and severe hepatic impairment (Child-Pugh class C).
The results show that Cmax and area AUCinf ratios for estetrol were ~1.7-fold and ~1.1-fold, respectively, in mild hepatic impairment versus subjects with normal hepatic function, ~1.9-fold and ~1-fold, respectively, in moderate hepatic impairment versus subjects with normal hepatic function, and ~5.4-fold and ~1.9-fold, respectively, in severe hepatic impairment versus subjects with normal hepatic function.
A study to evaluate the effect of renal disease on pharmacokinetics of estetrol was performed with a single oral dose of estetrol 18.9 mg administered in female subjects with normal renal function, mild renal impairment (absolute glomerular filtration rate (GFR <90 to ≥60 mL/min), moderate renal impairment (GFR <60 to ≥30 mL/min) and severe renal impairment (GFR <30 mL/min).
Cmax and AUCinf for estetrol were ~1.1-fold and ~1.7-fold, respectively, in mild renal impairment versus subjects with normal renal function; ~1.8-fold and ~2.3-fold, respectively, in moderate renal impairment versus subjects with normal renal function, and ~1.5-fold and ~2.3-fold, respectively, in severe renal impairment versus subjects with normal renal function.
Renal clearance (CLr) was decreased by 20% in the group with mild renal impairment, 40% in the group with moderate renal impairment, and 71% in the group with severe renal impairment compared to the group with normal renal function.
The study results indicate that the increase of estetrol plasma exposure in subjects with moderate and severe renal impairment compared to subjects with a normal renal function could be of clinical relevance.
No clinically relevant differences in the pharmacokinetics of estetrol between Japanese and Caucasian women have been observed after single dose administration of estetrol 14.2 mg.
Repeated dose toxicity studies with estetrol have indicated expected oestrogenic effects. In particular, reproduction toxicity studies revealed embryonic and foetotoxic effects in animals which are considered as species specific.
Estetrol is 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 have shown that estetrol may pose a risk to the aquatic environment and to the groundwater compartment.
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