Allopregnanolone Concentrations After Ascending Single Dose Administration of Progesterone to Healthy Volunteers

Abstract

Background

Postpartum depression (PPD) is associated with significant morbidity and mortality. It affects as many as 11.5% of women giving birth. Allopregnanolone (an endogenous progesterone metabolite) has been a promising avenue of clinical research for the treatment of PPD.

Aim

To assess the pharmacokinetics of allopregnanolone (Allo) following orally dosed progesterone in healthy volunteers. Secondary outcome was calculating the daily dose of progesterone needed to achieve the clinically meaningful concentration of 50 ng/mL Allo.

Methods

Single ascending dose study to measure plasma concentrations of Allo after 200, 400 and 600 mg doses of extended-release progesterone capsules. Secondary outcome was the safety and tolerability of extended-release progesterone capsules.

Results

We recruited 10 participants, 9 male and 1 female, mean (SD) age 38.7 (18.7) years. The maximum plasma concentration (C_max) of Allo was observed at 2 h. A linear relationship was fitted to the observations. Sedation was assessed at baseline, 1, 2, 4, 6 and 8 h after each dose. Sedation ratings increased at 1–2 h post-dose after all three progesterone doses, with the greatest increase after the 600 mg dose, and fell subsequently. Vital signs were unchanged, and no other adverse events were reported.

Conclusions

In this single ascending dose study has clarified that 400 mg four times/day of progesterone is required to achieve maximum plasma ALLO concentrations of 50 ng/mL. Tolerability and safety were acceptable for all doses of progesterone tested.