Objectives: Estetrol (E4) is a natural fetal estrogen. In this open-label, multiple-rising-dose study, the pharmacokinetic effects of E4 in postmenopausal women were investigated as a secondary objective.
Methods: In total, 49 postmenopausal women were randomized to receive either 2 mg E4 or 2 mg estradiol valerate (E2V) for 28 days, or were (non-randomized) assigned to 10, 20, or 40 mg E4. The main outcome measures were: E4 plasma concentrations at trough, and on days 1 and 28; and E4 pharmacokinetic parameters AUC, Cmax and tmax on days 1 and 28.
Results: After oral administration, E4 showed a very fast absorption, followed by a multiphasic elimination with an initial rapid decline, gradually continuing with a slower elimination, suggesting a long terminal half-life. Steady state was reached within 2 weeks of dosing and pharmacokinetic results were generally proportional to the dose. Estetrol concentrations on day 28 were slightly higher compared to day 1, indicating some accumulation.
Conclusion: The pharmacokinetic profile of estetrol is characterized by a very fast absorption phase, followed by an initial rapid decline, and a slow terminal elimination phase. Based on its kinetic properties, estetrol seems suitable for use as a once-daily oral drug.
Keywords: Estetrol; menopausal hormone treatment; pharmacokinetics.