Hull, L.Stuckey, B.G.A.Hartman, K.Zack, N.Friend, D.R.2024-10-222024-10-222023Menopause, 2023; 30(4):427-4361072-37141530-0374https://hdl.handle.net/2440/142908Objective: 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. Methods: Thiswas an open-label, three-arm(group) study. Thirty-two (32) healthy postmenopausalwomenwere recruited at twoAustralian sites. The average agewas 57.2 years (47-69 y). The first armreceived one ring for 28 days designed to release E2 at a rate of 80 μg/d and P4 at 4mg/d (80/4 IVR); the second armreceived a ring releasing E2 at 160 μg/d and P4 at 8mg/d (160/8 IVR). The third armreceived oral Estrofem (1mg E2) and Prometrium (100 mg P4) both daily for 29 days. Blood sampleswere taken predose then intensively over the first day (day 1) and periodically thereafter over the remaining 27 days.After removal of the rings on themorning of day 29, intensive sampleswere collected. Similar procedureswere conductedwithwomen enrolled in the oral group. The plasma samples were analyzed for E2, estrone (E1), and P4 using validated bioanalytical methods. Results: 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 from160/8 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. Conclusions: 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 newoption for hormone therapy for treatment of VMS and vaginal symptoms associated with menopause.en© 2023 by The North American Menopause SocietyEstradiol; Hormone; Hormone therapy; Menopause; Progesterone; Vaginal ringHumansEstradiolEstroneProgesteroneContraceptive Devices, FemaleMiddle AgedAustraliaFemaleJournal article10.1097/gme.00000000000021482024-05-06646663Hull, L. [0000-0003-1813-3971] [0000-0003-4660-4005]