MTN-001: randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments.
MTN-001: randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments.
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DOI：
10.1371/journal.pone.0055013
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bumpus NN
中科院分区：
文献类型：
--
作者：
Hendrix CW;Chen BA;Guddera V;Hoesley C;Justman J;Nakabiito C;Salata R;Soto-Torres L;Patterson K;Minnis AM;Gandham S;Gomez K;Richardson BA;Bumpus NN
替诺福韦的口服和阴道制剂作为人类免疫缺陷病毒（HIV）感染的暴露前预防（PrEP）已在男性和女性中表现出不同的功效，这促使评估药物浓度的变化作为解释。了解替诺福韦的浓度及其活性形式（二磷酸替诺福韦）在假定的阴道和直肠作用部位及其与多个其他解剖位置浓度的关系，可以为解释 PrEP 研究结果和规划未来 PrEP 药物开发提供关键信息。 MTN-001 旨在以配对交叉设计直接比较口服与阴道稳态替诺福韦在血液、阴道组织以及阴道和直肠液中的药代动力学。我们在美国 4 个和非洲 3 个临床研究中心招募了 144 名未感染 HIV 的女性，参与一项开放标签、3 期交叉研究，研究了三种不同的每日替诺福韦治疗方案，每种治疗方案持续 6 周（口服 300 毫克富马酸替诺福韦二吡呋酯，阴道 1% 替诺福韦凝胶 [40 毫克]，或两者同时使用）。阴道给药后的血清浓度比口服给药后低56倍（p<0.001）。 ≥90% 的阴道给药女性的阴道组织中替诺福韦二磷酸盐可以定量，而口服给药的女性中只有 19% 的女性可以定量替诺福韦二磷酸盐。与口服给药相比，阴道组织中替诺福韦二磷酸盐含量高 ≥130 倍（p<0.001）。阴道给药期间直肠液替诺福韦浓度高于仅口服给药期间测得的浓度（p<0.03）。与口服给药相比，阴道给药实现了低得多的血清浓度和高得多的阴道组织浓度。即使由于依从性差或处方给药频率较低而导致浓度差异 100 倍，替诺福韦阴道给药也应比口服给药提供更高的活性位点浓度和理论上更高的 PrEP 功效；相反，随机局部给药 PrEP 试验表明，替诺福韦抗病毒作用以外的因素会严重影响 PrEP 疗效。临床试验.gov NCT00592124
Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development. MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design. We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03). Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir’s antiviral effect substantially influence PrEP efficacy. ClinicalTrials.gov NCT00592124
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DOI：
10.1128/cdli.4.5.624-626.1997
发表时间：
1997-09-01
期刊：
CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY
影响因子：
--
作者：
Mohamed, AS;Becquart, P;Belec, L
通讯作者：
Belec, L
DOI：
10.1097/01.qai.0000167155.44980.e8
发表时间：
2005-08-01
影响因子：
3.6
作者：
Hawkins, T;Veikley, W;Kearney, BP
通讯作者：
Kearney, BP
影响因子：
9.4
作者：
Mitchell, Caroline;Paul, Kathleen;Hitti, Jane
通讯作者：
Hitti, Jane
影响因子：
3.7
作者：
Keller MJ;Madan RP;Torres NM;Fazzari MJ;Cho S;Kalyoussef S;Shust G;Mesquita PM;Louissaint N;Chen J;Cohen HW;Diament EC;Lee AC;Soto-Torres L;Hendrix CW;Herold BC
通讯作者：
Herold BC
DOI：
10.1126/science.1193748
发表时间：
2010-09-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Abdool Karim Q;Abdool Karim SS;Frohlich JA;Grobler AC;Baxter C;Mansoor LE;Kharsany AB;Sibeko S;Mlisana KP;Omar Z;Gengiah TN;Maarschalk S;Arulappan N;Mlotshwa M;Morris L;Taylor D;CAPRISA 004 Trial Group
通讯作者：
CAPRISA 004 Trial Group