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Abstract：
BACKGROUND: Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy.
METHODS: Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported.
RESULTS: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12).
CONCLUSIONS: The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.
METHODS: Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported.
RESULTS: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12).
CONCLUSIONS: The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.
摘要：
背景：配制用于同时递送两种药物的阴道环具有用户控制的潜力，双重预防艾滋病毒和怀孕的长效方法。
方法：两项1期随机试验（MTN-030/IPM041和MTN-044/IPM053/CCN019）分别纳入24和25名健康者，HIV阴性参与者评估安全性，药代动力学，和阴道出血与使用设计用于90天使用的包含200mgdapivirine（DPV）和320mg左炔诺孕酮（LNG）的阴道环有关。MTN-030/IPM041将DPV/LNG环与使用14天的仅DPV环(200mg)进行比较。MTN-044/IPM053/CCN019比较了连续或循环使用DPV/LNG环超过90天的使用。通过记录不良事件(AE)评估安全性。血浆中DPV和LNG浓度定量，宫颈阴道液，和宫颈组织。阴道出血为自我报告。
结果：患有DPV/LNG环的泌尿生殖系统不良事件≥2级或≥3级不良事件的参与者比例无差异。DPV环使用(p=.22)，或DPV/LNG环连续与循环使用(p=.67)。与仅使用DPV的环相比,在DPV/LNG的使用者中观察到更高的血浆DPV浓度(Cmaxp=0.049;AUCp=0.091)。血浆DPV和LNG浓度与连续和循环使用相当(Cmaxp=0.74;AUCp=0.25)。循环使用，清除后2天,血浆DPV的最低点浓度中位数约为300pg/mL,宫颈阴道液DPV浓度的t1/2中位数为5.76小时(n=3).连续和循环使用者的总体出血经历没有差异(p=0.12)。
结论：延长的DPV/LNG环有良好的耐受性，使用时观察到的血浆和宫颈阴道液中的DPV浓度持续超过先前DPV环疗效研究中观察到的浓度。血浆中的LNG浓度与其他有效的基于LNG的避孕药相当。生殖器DPV浓度的半衰期短，因此在去除环后不能很好地维持。
方法：两项1期随机试验（MTN-030/IPM041和MTN-044/IPM053/CCN019）分别纳入24和25名健康者，HIV阴性参与者评估安全性，药代动力学，和阴道出血与使用设计用于90天使用的包含200mgdapivirine（DPV）和320mg左炔诺孕酮（LNG）的阴道环有关。MTN-030/IPM041将DPV/LNG环与使用14天的仅DPV环(200mg)进行比较。MTN-044/IPM053/CCN019比较了连续或循环使用DPV/LNG环超过90天的使用。通过记录不良事件(AE)评估安全性。血浆中DPV和LNG浓度定量，宫颈阴道液，和宫颈组织。阴道出血为自我报告。
结果：患有DPV/LNG环的泌尿生殖系统不良事件≥2级或≥3级不良事件的参与者比例无差异。DPV环使用(p=.22)，或DPV/LNG环连续与循环使用(p=.67)。与仅使用DPV的环相比,在DPV/LNG的使用者中观察到更高的血浆DPV浓度(Cmaxp=0.049;AUCp=0.091)。血浆DPV和LNG浓度与连续和循环使用相当(Cmaxp=0.74;AUCp=0.25)。循环使用，清除后2天,血浆DPV的最低点浓度中位数约为300pg/mL,宫颈阴道液DPV浓度的t1/2中位数为5.76小时(n=3).连续和循环使用者的总体出血经历没有差异(p=0.12)。
结论：延长的DPV/LNG环有良好的耐受性，使用时观察到的血浆和宫颈阴道液中的DPV浓度持续超过先前DPV环疗效研究中观察到的浓度。血浆中的LNG浓度与其他有效的基于LNG的避孕药相当。生殖器DPV浓度的半衰期短，因此在去除环后不能很好地维持。
