FAME-04: A Phase 1 trial to assess the safety, acceptability, pharmacokinetics and pharmacodynamics of film and gel formulations of tenofovir
FAME-04: A Phase 1 trial to assess the safety, acceptability, pharmacokinetics and pharmacodynamics of film and gel formulations of tenofovir
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DOI：
10.1002/jia2.25156
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发表时间：
2018-08-13
影响因子：
6
通讯作者：
Hillier, Sharon L.
中科院分区：
文献类型：
--
作者：
Bunge, Katherine E.;Dezzutti, Charlene S.;Hillier, Sharon L.
简介：快速溶解的阴道膜制剂将抗逆转录病毒药物直接释放到阴道液中，可能与凝胶一样有效，但更容易被妇女接受。在这项一期阴道膜研究中，比较了两种剂量的替诺福韦（TFV）膜和TFV 1%凝胶与相应安慰剂制剂的安全性、可接受性、药代动力学和药效学。方法：78名健康的HIV阴性女性随机接受每日自插入阴道膜（TFV 10 mg、TFV 40 mg或安慰剂）或阴道凝胶（TFV 1% [40 mg]或安慰剂）4 mL，为期7天。使用Fisher精确检验比较与研究产品相关的2级及以上不良事件（ae）。最后一次用药前和用药后2小时测定血浆TFV浓度。在最后一次给药后2小时进行配对宫颈和阴道组织活检，以测定二磷酸替诺福韦（ttfv - dp）浓度，并在体外激发试验中暴露于HIV。通过问卷评估可接受性。结果：仅有1例2级及以上相关AE为主要终点；它发生在安慰剂凝胶组。90%的参与者发生ae；大多数（91%）为1级。不同研究组的ae相似。40 mg TFV膜组和TFV凝胶组血浆中TFV浓度、宫颈和阴道组织中TFV- dp浓度相当。宫颈组织中tv - dp浓度与病毒复制减少有显著关系。薄膜使用者比凝胶使用者更不可能报告产品泄漏（66%比100%，p < 0.001）。结论：涂片安全，耐受性好。此外，薄膜以类似凝胶的浓度将TFV输送到粘膜组织，足以在体外阻断生殖器组织的HIV感染。
Introduction: Fast-dissolving vaginal film formulations release antiretroviral drugs directly into vaginal fluid and may be as efficient at drug delivery yet more acceptable to women than gels. In this Phase 1 vaginal film study, the safety, acceptability, pharmacokinetics and pharmacodynamics of two doses of tenofovir (TFV) film and TFV 1% gel were compared to corresponding placebo formulations.Methods: Seventy-eight healthy HIV negative women were randomized to self-insert daily vaginal film (10 mg TFV, 40 mg TFV or placebo) or 4 mL of vaginal gel (TFV 1% [40 mg] or placebo) for seven days. Grade 2 and higher adverse events (AEs) related to study product were compared across study arms using Fisher's exact test. Plasma TFV concentrations were measured before and 2 hours after last product use. Paired cervical and vaginal tissue biopsies obtained 2 hours after the last dose were measured to determine tenofovir diphosphate (TFV-DP) concentrations and exposed to HIV in an ex vivo challenge assay. Acceptability was assessed through questionnaire.Results: There was only one grade 2 or higher related AE, the primary endpoint; it occurred in the placebo gel arm. AEs occurred in 90% of participants; the majority (91%) were grade 1. AEs were similar across study arms. TFV concentrations in plasma and TFV-DP concentrations in cervical and vaginal tissues were comparable between 40 mg TFV film and the TFV gel groups. There was a significant relationship between reduced viral replication and TFV-DP concentrations in cervical tissues. Film users were less likely to report product leakage than gel users (66% vs. 100%, p < 0.001).Conclusions: Films were safe and well tolerated. Furthermore, films delivered TFV to mucosal tissues at concentrations similar to gel and were sufficient to block HIV infection of genital tissue ex vivo.