Hull Louise, Stuckey Bronwyn G A, Hartman Kimberly, Zack Nadene, Friend David R
From the PARC Clinical Research, University of Adelaide, Adelaide, Australia.
Keogh Institute for Medical Research, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, University of Western Australia, Nedlands, Australia.
Menopause. 2023 Apr 1;30(4):427-436. doi: 10.1097/GME.0000000000002148. Epub 2023 Jan 22.
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.
本研究旨在开发一种单剂量阴道环（IVR），其含有17β-雌二醇（E2）和孕酮（P4）的组合，用于治疗血管舒缩症状（VMS）和绝经后泌尿生殖综合征，同时提供子宫内膜保护。本研究的目的是在一项1期临床试验中评估DARE-HRT1（一种持续释放E2和P4的28天阴道环）的药代动力学。
这是一项开放标签、三臂（组）研究。在澳大利亚的两个地点招募了32名健康的绝经后女性。平均年龄为57.2岁（47 - 69岁）。第一组接受一个释放28天的阴道环，其设计为以80μg/天的速率释放E2和4mg/天的P4（80/4阴道环）；第二组接受一个以160μg/天的速率释放E2和8mg/天的P4的阴道环（160/8阴道环）。第三组每天口服Estrofem（1mg E2）和Prometrium（100mg P4），共29天。在给药前、第1天（第1天）进行密集采血，此后在剩余的27天内定期采血。在第29天早晨取出阴道环后，进行密集采样。口服组的女性也进行类似的操作。使用经过验证的生物分析方法分析血浆样本中的E2、雌酮（E1）和P4。
80/4阴道环的E2和P4的基线调整后稳态血浆水平分别为20.4±17.1pg/mL和1.32±0.19ng/mL（n = 10）。160/8阴道环的E2和P4的基线调整后稳态血浆水平分别为30.9±8.7pg/mL和2.08±0.50ng/mL（n = 10）。口服组在第29天的E2和P4的基线调整后平均血浆浓度分别为35.4±11.2pg/mL和0.79±0.72ng/mL（n = 11）。80/4阴道环和160/8阴道环的E1的基线调整后稳态分别为22.1±16.6pg/mL（n = 10）和25.2±12.3pg/mL（n = 10）。口服组中E1的基线调整后浓度为209±67.7ng/mL（n = 11）。阴道环耐受性良好，未报告严重不良事件。
80/4阴道环和160/8阴道环产生的E2稳态浓度与美国食品药品监督管理局批准用于治疗VMS和绝经后泌尿生殖症状的药品相似。本研究的E2浓度支持DARE-HRT1作为治疗VMS和绝经相关阴道症状的激素治疗的一种有前景的新选择的潜力。
