Pharmacokinetics of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women

Abstract

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, C_max and t_max 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

Conflict of interest

H. C. B. is the CEO and a shareholder of Pantarhei Bioscience BV. C. V. and Y. Z. are employees, and M. V. is a former employee, of Pantarhei Bioscience BV. J. M. F. is a consultant of Mithra Pharmaceuticals. K. G. D. occasionally serves on advisory boards and has been an invited speaker at scientific meetings for Bayer, MSD/Merck, HRA Pharma, ExelGyn, and Gedeon Richter on an ad hoc basis.

Source of funding

The study was funded by Pantarhei Bioscience BV. Medical writing support was provided by Mireille Gerrits, PharmD, at Terminal 4 Communications.