A Phase 1 Randomized, Blinded Comparison of the Pharmacokinetics and Colonic Distribution of Three Candidate Rectal Microbicide Formulations of Tenofovir 1% Gel with Simulated Unprotected Sex (CHARM-02)
A Phase 1 Randomized, Blinded Comparison of the Pharmacokinetics and Colonic Distribution of Three Candidate Rectal Microbicide Formulations of Tenofovir 1% Gel with Simulated Unprotected Sex (CHARM-02)
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DOI：
10.1089/aid.2015.0098
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发表时间：
2015-11-01
影响因子：
1.5
通讯作者：
Hendrix, Craig W.
中科院分区：
文献类型：
--
作者：
Hiruy, Hiwot;Fuchs, Edward J.;Hendrix, Craig W.
CHARM-02是一项交叉、双盲、随机试验，旨在比较三种不同渗透压的直肠应用替诺福韦1%凝胶候选直肠杀微生物剂的安全性和药代动力学：阴道制剂（VF）（3111 mOsmol/kg）、甘油减少阴道制剂（RGVF）（836 mOsmol/kg）和等渗透压直肠特异性制剂（RF）（479 mOsmol/kg）。受试者（n = 9）接受单次4 ml放射性标记剂量的每种凝胶两次，一次有和一次没有模拟无保护的接受性肛交（RAI）。评价了替诺福韦的安全性、血浆药代动力学、结肠小分子通透性和药物和病毒替代物下消化道分布的SPECT/CT成像。任何产品均未报告3级或4级不良事件。总体而言，VF组的2级不良事件多于RF组（p = 0.006）和RGVF组（p = 0.048）。在没有模拟的无保护RAI的情况下，与RF和RGVF相比，VF的全身替诺福韦暴露量高达3.8倍，药物替代物的结肠渗透性高26至234倍，结肠腔内的近端迁移高1.5至2倍。在模拟的无保护RAI中观察到类似的趋势，但大多数没有达到统计学显著性。SPECT分析显示86%（标准差19%）的药物替代物与病毒替代物在结肠腔中共定位。RGVF和RF制剂之间没有显著差异，除了在不存在模拟未保护RAI的情况下RGVF的血浆替诺福韦浓度较高。与RF和RGVF制剂相比，VF具有最多的不良事件、最高的血浆替诺福韦浓度、更大的药物替代物的粘膜渗透性和最近端的结肠腔迁移。RF和RGVF制剂之间无重大差异。同时评估毒性、全身和管腔药代动力学以及药物和病毒替代物的共定位实质上为直肠杀微生物剂产品开发提供了信息。
CHARM-02 is a crossover, double-blind, randomized trial to compare the safety and pharmacokinetics of three rectally applied tenofovir 1% gel candidate rectal microbicides of varying osmolalities: vaginal formulation (VF) (3111 mOsmol/kg), the reduced glycerin vaginal formulation (RGVF) (836 mOsmol/kg), and an isoosmolal rectal-specific formulation (RF) (479 mOsmol/kg). Participants (n = 9) received a single, 4 ml, radiolabeled dose of each gel twice, once with and once without simulated unprotected receptive anal intercourse (RAI). The safety, plasma tenofovir pharmacokinetics, colonic small molecule permeability, and SPECT/CT imaging of lower gastrointestinal distribution of drug and virus surrogate were assessed. There were no Grade 3 or 4 adverse events reported for any of the products. Overall, there were more Grade 2 adverse events in the VF group compared to RF (p = 0.006) and RGVF (p = 0.048). In the absence of simulated unprotected RAI, VF had up to 3.8-fold greater systemic tenofovir exposure, 26- to 234-fold higher colonic permeability of the drug surrogate, and 1.5- to 2-fold greater proximal migration in the colonic lumen, when compared to RF and RGVF. Similar trends were observed with simulated unprotected RAI, but most did not reach statistical significance. SPECT analysis showed 86% (standard deviation 19%) of the drug surrogate colocalized with the virus surrogate in the colonic lumen. There were no significant differences between the RGVF and RF formulation, with the exception of a higher plasma tenofovir concentration of RGVF in the absence of simulated unprotected RAI. VF had the most adverse events, highest plasma tenofovir concentrations, greater mucosal permeability of the drug surrogate, and most proximal colonic luminal migration compared to RF and RGVF formulations. There were no major differences between RF and RGVF formulations. Simultaneous assessment of toxicity, systemic and luminal pharmacokinetics, and colocalization of drug and viral surrogates substantially informs rectal microbicide product development.