As part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone® (NES)) combined with one of three different estradiol (E_2) doses.
A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200 μg/day] plus E_2, either 10 μg/day, 20 μg/day, or 40 μg/day in healthy reproductive-age women with regular cycles. Participants provided blood samples twice weekly for NES and E_2 levels during the first 60 days (ring 1) and the last 30 days (ring 2) of use. A subset underwent formal PK assessments at ring initiation, ring exchange (limited PK), and study completion.
The main study enrolled 197 women; 22 participated in the PK substudy. Baseline characteristics between the main and PK participants were comparable, with an average BMI of 25.8 kg/m^2 (SD 4.3). In the PK substudy, all three rings showed similar NES PK: mean area under the curve (AUC_(0–72)) 34,181 pg*day/mL; concentration maximum (Cmax) 918 pg/mL; time to maximum concentration (Tmax) 3.5 h. For E_2, the Cmax occurred at 2 h, and was significantly higher with the 20 ug/day ring (mean 390 pg/mL); 10ug/day, 189 pg/mL, p=.003; 40 ug/day, 189 pg/mL, p<.001), and declined rapidly to≤50 pg/mL for all doses by 24 h. For all subjects, the median E_2 levels remained under 35 pg/mL during treatment.
PK parameters of NES were not affected when paired with different doses of E_2, but E_2 levels from all three doses were lower than anticipated and no dose response was observed.
While these novel estradiol-releasing combination contraceptive vaginal rings provided sustained release of contraceptive levels of Nestorone over 90 days, the E_2 levels achieved were not consistent with bone protection, and a dose–response was not observed.