Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol: pharmacokinetics from a dose-finding study

Background: 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 (R) (NES)) combined with one of three different estradiol (E-2) doses. Study design: A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200 mcg/day] plus E-2, either 10 mcg/day, 20 mcg/day, or 40 mcg/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. Results: 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 (C-max) 918 pg/mL; time to maximum concentration (T-max) 3.5 h. For E-2, the C-max occurred at 2 h, and was significantly higher with the 20 mcg/day ring (mean 390 pg/mL); 10 mcg/day, 189 pg/mL, p=.003; 40 mcg/day, 189 pg/mL, p<.001), and declined rapidly tc <= 50 pg/mL for all doses by 24 h. For all subjects, the median E-2 levels remained under 35 pg/mL during treatment. Conclusion: 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. (C) 2018 Elsevier Inc. All rights reserved.