A Phase 1 Trial to Assess the Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics of a Novel Dapivirine Vaginal Film
A Phase 1 Trial to Assess the Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics of a Novel Dapivirine Vaginal Film
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DOI：
10.1097/qai.0000000000000897
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发表时间：
2016-04-15
影响因子：
3.6
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.
背景：薄膜可以有效地将抗逆转录病毒药物输送到粘膜组织。在这项用于传递非核苷逆转录酶抑制剂达匹韦林的阴道膜剂的首次人体试验中，比较了膜剂和凝胶制剂与安慰剂的安全性、药代动力学和药效学。方法：61名健康的HIV阴性妇女被随机分为每日服用达匹韦林(0.05%)、安慰剂凝胶、达匹韦林(1.25 mg)或安慰剂膜剂7天。比较了参与者经历与研究产品相关的2级和更高不良事件的比例。测定达匹韦林的血药浓度。最后一次服药后2小时内获得的宫颈和阴道组织活检标本测量组织药物浓度，并在体外激发试验中暴露于HIV。结果：安慰剂组发生了2例2级相关不良事件。随机服用凝胶和薄膜产品的妇女在宫颈和阴道组织中的达匹韦林浓度比血浆中高4对数(10)。尽管凝胶和薄膜使用者的血浆达匹韦林浓度相当，但凝胶使用者组织中的达匹韦林浓度是薄膜使用者的3-5倍。在体外激发试验中，随机服用达匹韦林薄膜或凝胶的妇女的阴道组织中艾滋病毒复制显著减少；此外，组织药物浓度与艾滋病毒保护高度相关。女性评价这种薄膜更舒适，渗漏更少，但发现它比凝胶更难插入。讨论：薄膜和凝胶都能提供足够浓度的达匹韦林，足以在体外阻断HIV。这项概念验证研究表明，杀菌剂的薄膜配方值得进一步研究。
Background:Films may deliver antiretroviral drugs efficiently to mucosal tissues. In this first in-human trial of a vaginal film for delivering the nonnucleoside reverse transcriptase inhibitor dapivirine, safety, pharmacokinetics, and pharmacodynamics of film and gel formulations were compared with placebo.Methods:Sixty-one healthy HIV-negative women were randomized to daily dapivirine (0.05%) or placebo gel, or dapivirine (1.25 mg) or placebo film for seven days. The proportion of participants experiencing grade 2 and higher adverse events related to study product were compared. Plasma dapivirine concentrations were quantified. Paired cervical and vaginal tissue biopsies obtained similar to 2 hours after the last dose were measured for tissue drug concentration and exposed to HIV in an ex vivo challenge assay.Results:Two grade 2 related adverse events occurred in the placebo film group. Women randomized to gel and film products had 4 log(10) higher of dapivirine in cervical and vaginal tissues than plasma. Although gel and film users had comparable plasma dapivirine concentrations, tissue concentrations of dapivirine were 3-5 times higher in the gel users when compared with film users. HIV replication in the ex vivo challenge assay was significantly reduced in vaginal tissues from women randomized to dapivirine film or gel; furthermore, tissue drug concentrations were highly correlated with HIV protection. Women rated the film more comfortable with less leakage but found it more difficult to insert than gel.Discussion:Both film and gel delivered dapivirine at concentrations sufficient to block HIV ex vivo. This proof-of-concept study suggests film formulations for microbicides merit further investigation.