Dapivirine (DPV), formulated as vaginal ring, demonstrated HIV risk reduction. MTN-026 explored DPV, formulated as rectal gel, for safety, pharmacokinetics (PK), and acceptability. HIV-uninfected men and women aged 18–45 years were enrolled at United States and Thailand sites and randomized 2:1 to receive DPV 0.05% or placebo gel via rectal applicator. A single-dose phase was followed by seven observed daily doses. Plasma and fluid and tissue from both rectum and cervix were collected at baseline and after the final dose over 72 h for PK, ex-vivo HIV-1 biopsy challenge, histology, and flow cytometry. Twenty-eight participants were randomized; 2 terminated early; 9 were female and 19 male; 12 were white, 11 Asian, 4 black, and 1 other race/ethnicity. Mean age was 28.5 and 34.2 years in the DPV and placebo arms, respectively. Thirty adverse events occurred (all Grade 1 or 2, except one unrelated Grade 3) without study arm differences. DPV rectal tissue concentrations [median (interquartile range)] 0.5–1 and 2 h after a single dose were 256 ng/g [below the lower limit of quantification (BLQ)–666] and BLQ (BLQ–600), respectively, then BLQ (BLQ–BLQ) from 24 to 72 h; concentrations following multiple doses were similar. The largest median DPV plasma concentrations were 0.33 ng/mL (0.15–0.48) after one dose and 0.40 (0.33–0.49) after seven doses. The DPV rectal gel was acceptable and without safety concerns. While DPV plasma concentrations were similar to the vaginal ring, rectal tissue concentrations were well below vaginal ring tissue concentrations, suggesting need for reformulation.

中文翻译：

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Dapivirine 凝胶 (0.05%) 直肠给药至 HIV-1 血清阴性成人的随机、双盲、安慰剂对照、1 期安全性和药代动力学研究 (MTN-026)

Dapivirine (DPV)，配制为阴道环，证明可以降低 HIV 风险。MTN-026 探索了 DPV（配制为直肠凝胶）的安全性、药代动力学 (PK) 和可接受性。年龄在 18-45 岁之间的未感染 HIV 的男性和女性在美国和泰国的研究中心被纳入研究，并以 2:1 的比例随机分配，通过直肠涂药器接受 DPV 0.05% 或安慰剂凝胶。单剂量阶段之后是七次观察到的每日剂量。在基线时和在 72 小时的最后剂量后收集来自直肠和子宫颈的血浆和液体以及组织，用于 PK，离体HIV-1 活检挑战、组织学和流式细胞术。二十八名参与者被随机分配；2 提前终止；9名女性，19名男性；12 名白人、11 名亚裔、4 名黑人和 1 名其他种族/族裔。DPV 组和安慰剂组的平均年龄分别为 28.5 岁和 34.2 岁。发生了 30 起不良事件（全部为 1 级或 2 级，除了 1 起不相关的 3 级事件），研究组没有差异。单次给药后 0.5-1 小时和 2 小时的 DPV 直肠组织浓度 [中位数（四分位数间距）] 分别为 256 ng/g [低于定量下限 (BLQ)–666] 和 BLQ (BLQ–600)，然后BLQ (BLQ–BLQ) 从 24 到 72 小时；多次给药后的浓度相似。一剂后最大中位 DPV 血浆浓度为 0.33 ng/mL (0.15–0.48)，七剂后为 0.40 (0.33–0.49)。DPV 直肠凝胶是可以接受的，没有安全问题。虽然 DPV 血浆浓度与阴道环相似，但直肠组织浓度远低于阴道环组织浓度，表明需要重新配制。