First human exposure to exogenous single-dose oral estetrol in early postmenopausal women

To evaluate the safety, tolerability, pharmacokinetics and effect on gonadotropins of a single escalating dose of estetrol (E(4)).

A first-in-human study with E(4) was performed in healthy early postmenopausal women. Four single doses of 0.1, 1, 10 and 100 mg E(4) were evaluated in study groups of eight subjects each, of whom six received active treatment and two placebo treatment. Safety and tolerability were documented and several pharmacokinetic parameters were determined, as were the plasma levels of the gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) (pharmacodynamics). The next higher-dose group was enrolled after pharmacokinetic evaluation and confirmed safety of the previous group.

After oral intake, the plasma concentrations of E(4) showed a steep increase, followed by a sharp decline and a secondary increase at all dose levels. Estetrol was distributed and reabsorbed during the first 18 h after oral intake. The terminal elimination phase started at 24 h post-dose and half-life (t((1/2))) ranged in the 10 mg group between 19 and 40 h (mean 28.4 h, median 28.8 h) and in the 100 mg group between 18 and 60 h (mean 28.0 h, median 20 h), indicating a dose independency of the half-life. The pharmacokinetic parameters also demonstrated a high dose-response relationship and showed excellent consistency and low variability within the dose groups. The pharmacodynamic data showed a dose-dependent inhibition of plasma LH levels by E(4). A profound and sustained inhibition of FSH levels, lasting over 168 h, was observed in the 100 mg dose group (FSH was not measured in the other dose groups). Estetrol was well tolerated at all dose levels and no safety problems were encountered.

Estetrol is orally absorbed and bioavailable with a strong dose-response relationship suggesting high oral bioavailability. Interindividual variations of plasma levels are low. The elimination half-life of 28 h suggests slow metabolism of E(4). The pharmacodynamic pattern complies with enterohepatic recirculation. Estetrol has a profound central inhibitory and dose-dependent effect on gonadotropins, confirming its biological potency.