Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design
Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design
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DOI：
10.1097/qai.0000000000000996
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发表时间：
2016-08-15
影响因子：
3.6
通讯作者：
Kashuba, Angela D. M.
中科院分区：
文献类型：
--
作者：
Cottrell, Mackenzie L.;Prince, Heather M. A.;Kashuba, Angela D. M.
背景：定量组织药物浓度可以在药物开发过程中获得重要信息，但使药代动力学研究设计复杂化。直接抽吸（宫颈阴道液; CVF）或拭子（直肠液; RF）收集的粘液可能被用作组织浓度替代品，但这些关系没有很好的characteristic.Methods：四十九名健康女性，给予单次口服剂量的替诺福韦，马拉韦罗，恩曲他滨，或雷特格韦在50%-200%的治疗剂量，提供了13血浆，12 CVF，12 RF和一个宫颈，阴道和直肠组织活检超过48小时。这些配对样本之间的关系，其特征在于线性和多元线性回归。结果：除雷特格韦（r（2）= 0.08，P = 0.19）外，所有抗逆转录病毒药物的CVF暴露量均随剂量线性增加（r（2）0.23，P 0.02）。RF中，只有恩曲他滨随剂量线性增加（r（2）= 0.27，P = 0.01）。对于所有抗逆转录病毒药物，CVF和RF浓度与粘膜组织浓度显著相关（女性生殖道r（2）0.37，直肠组织r（2）0.50，P 0.001）。在最终的多变量模型中，血浆和液体浓度均与所有抗逆转录病毒药物的FGT浓度相关（r（2）0.81，P < 0.001）。在直肠组织中也观察到同样的结果（r（2）0.58，P < 0.001），但替诺福韦除外，其RF单独预测组织浓度（r（2）= 0.91，P < 0.001）。结论：粘液与组织浓度呈正相关，在大多数情况下，包括血浆浓度在内的回归模型得到改善。CVF（而非RF）中的剂量线性表明下胃肠道组织中存在饱和过程。这些结果表明，粘膜液和血浆浓度可用于定性推断这些抗逆转录病毒药物的组织浓度。
Background:Quantifying tissue drug concentrations can yield important information during drug development, but complicates pharmacokinetic study design. Mucosal fluids collected by direct aspiration (cervicovaginal fluid; CVF) or swab (rectal fluid; RF) might be used as tissue concentration surrogates, but these relationships are not well characterized.Methods:Forty-nine healthy women, given a single oral dose of tenofovir, maraviroc, emtricitabine, or raltegravir at 50%-200% of the treatment dose, provided 13 plasma, 12 CVF, 12 RF and one cervical, vaginal and rectal tissue biopsy over 48 hours. Relationships between these paired samples were characterized by linear and multiple linear regression. Adjusted r(2) values were used to select the final predictive models.Results:CVF exposure increased linearly with dose for all antiretrovirals (r(2) 0.23, P 0.02) except raltegravir (r(2) = 0.08, P = 0.19). In RF, only emtricitabine increased linearly with dose (r(2) = 0.27, P = 0.01). For all antiretrovirals, CVF and RF concentrations significantly correlated with mucosal tissue concentrations (female genital tract r(2) 0.37, rectal tissue r(2) 0.50, P 0.001). In the final multivariate models, plasma and fluid concentrations were both associated with FGT concentrations for all antiretrovirals (r(2) 0.81, P < 0.001). The same was noted for rectal tissue (r(2) 0.58, P < 0.001) except for tenofovir, for which RF alone was predictive of tissue concentration (r(2) = 0.91, P < 0.001).Conclusions:Mucosal fluids were positively correlated with tissue concentrations and including plasma concentrations improved the regression models in most cases. Dose linearity in CVF, but not RF, suggests a saturation process in lower gastrointestinal tract tissue. These findings suggest that mucosal fluid and plasma concentrations may be used for qualitative inference of tissue concentrations for these antiretrovirals.