Evaluation of 28-day estradiol and progesterone vaginal rings in a phase 1 clinical pharmacokinetic study.

Abstract

The aim of this work is to develop a combination of 17β-estradiol (E2) and progesterone (P4) in a single-dose intravaginal ring (IVR) for the treatment of vasomotor symptoms (VMS) and genitourinary syndrome of menopause while providing endometrial protection. The objective of this study was to evaluate DARE-HRT1, a 28-day IVR that continuously delivers E2 and P4, in a phase 1 clinical trial to assess its pharmacokinetics. This was an open-label, three-arm (group) study. Thirty-two (32) healthy postmenopausal women were recruited at two Australian sites. The average age was 57.2 years (47-69 y). The first arm received one ring for 28 days designed to release E2 at a rate of 80 μg/d and P4 at 4 mg/d (80/4 IVR); the second arm received a ring releasing E2 at 160 μg/d and P4 at 8 mg/d (160/8 IVR). The third arm received oral Estrofem (1 mg E2) and Prometrium (100 mg P4) both daily for 29 days. Blood samples were taken predose then intensively over the first day (day 1) and periodically thereafter over the remaining 27 days. After removal of the rings on the morning of day 29, intensive samples were collected. Similar procedures were conducted with women enrolled in the oral group. The plasma samples were analyzed for E2, estrone (E1), and P4 using validated bioanalytical methods. The baseline-adjusted steady-state plasma levels of E2 and P4 from 80/4 IVR were 20.4 ± 17.1 pg/mL and 1.32 ± 0.19 ng/mL (n = 10), respectively. The baseline-adjusted steady-state plasma levels of E2 and P4 from 160/8 IVR were 30.9 ± 8.7 pg/mL and 2.08 ± 0.50 ng/mL (n = 10), respectively. The baseline-adjusted average plasma concentrations of E2 and P4 at day 29 of the oral group were 35.4 ± 11.2 pg/mL and 0.79 ± 0.72 ng/mL (n = 11), respectively. The baseline-adjusted steady state of E1 from the 80/4 IVR and the 160/8 IVR were 22.1 ± 16.6 pg/mL (n = 10) and 25.2 ± 12.3 pg/mL (n = 10), respectively. The baseline-adjusted concentration of E1 in the oral arm was 209 ± 67.7 ng/mL (n = 11). The IVR were well tolerated, and no serious adverse events were reported. The 80/4 IVR and 160/8 IVR gave similar steady-state concentrations of E2 as seen with drug products approved by the US Food and Drug Administration for treatment of VMS and genitourinary symptoms of menopause. The E2 concentrations of this study support the potential of DARE-HRT1, a promising new option for hormone therapy for treatment of VMS and vaginal symptoms associated with menopause.