Bunge Katherine E, Dezzutti Charlene S, Rohan Lisa C, Hendrix Craig W, Marzinke Mark A, Richardson-Harman Nicola, Moncla Bernard J, Devlin Brid, Meyn Leslie A, Spiegel Hans M L, Hillier Sharon L
*Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA; †Magee-Womens Research Institute, Pittsburgh, PA; ‡Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA; §Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; ‖Alpha StatConsult, Damascus, MD; ¶International Partnership for Microbicides, Silver Spring, MD; and #HJF-DAIDS, a Division of The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Contractor to National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Rockville, MD.
J Acquir Immune Defic Syndr. 2016 Apr 15;71(5):498-505. doi: 10.1097/QAI.0000000000000897.
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.
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 ∼2 hours after the last dose were measured for tissue drug concentration and exposed to HIV in an ex vivo challenge assay.
Two grade 2 related adverse events occurred in the placebo film group. Women randomized to gel and film products had 4 log10 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.
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.
薄膜可能将抗逆转录病毒药物有效地递送至粘膜组织。在这项首次针对用于递送非核苷类逆转录酶抑制剂地瑞那韦的阴道薄膜的人体试验中，将薄膜和凝胶制剂的安全性、药代动力学及药效学与安慰剂进行了比较。
61名健康的HIV阴性女性被随机分为每日使用地瑞那韦（0.05%）或安慰剂凝胶，或地瑞那韦（1.25毫克）或安慰剂薄膜，为期7天。比较了发生与研究产品相关的2级及以上不良事件的参与者比例。对地瑞那韦的血浆浓度进行了定量分析。在最后一剂后约2小时获取的配对宫颈和阴道组织活检样本，测定其组织药物浓度，并在体外激发试验中使其暴露于HIV。
安慰剂薄膜组发生了两例2级相关不良事件。随机分配至凝胶和薄膜产品组的女性，其宫颈和阴道组织中的地瑞那韦浓度比血浆中高4个对数10。虽然使用凝胶和薄膜的女性血浆地瑞那韦浓度相当，但与使用薄膜的女性相比，使用凝胶的女性地瑞那韦的组织浓度高3至5倍。在体外激发试验中，随机分配至地瑞那韦薄膜或凝胶组的女性阴道组织中的HIV复制显著减少；此外，组织药物浓度与HIV防护高度相关。女性认为薄膜更舒适，渗漏更少，但发现其比凝胶更难插入。
薄膜和凝胶均能以足以在体外阻断HIV的浓度递送地瑞那韦。这项概念验证研究表明，用于杀微生物剂的薄膜制剂值得进一步研究。
