Tenofovir, Emtricitabine, and Tenofovir Diphosphate in Dried Blood Spots for Determining Recent and Cumulative Drug Exposure
Tenofovir, Emtricitabine, and Tenofovir Diphosphate in Dried Blood Spots for Determining Recent and Cumulative Drug Exposure
复制标题
DOI：
10.1089/aid.2012.0089
复制
发表时间：
2013-02-01
影响因子：
1.5
通讯作者：
Anderson, Peter L.
中科院分区：
文献类型：
--
作者：
Castillo-Mancilla, Jose R.;Zheng, Jia-Hua;Anderson, Peter L.
替诺福韦(TFV)富马酸异丙酯(TDF)+/-恩曲他滨(FTC)广泛用于HIV的治疗和化学预防，但不同的依从性可能导致不理想的反应。量化依从性的方法将使干预措施能够改善治疗和预防结果。我们的目标是描述TFV-二磷酸(TFV-DP)和FTC-三磷酸(FTC-TP)在红细胞(RBC)和外周血单核细胞(PBMC)中的药代动力学；将RBC分析扩展到干血斑(DBS)；并模拟RBC/DBS监测如何为最近和累积的药物暴露/依从性提供信息。对17名HIV阴性成人进行了为期30天的每日口服TDF/FTC的药代动力学研究，共5次。在冲洗期的第30天停止给药，并在第35、45和60天采集血液。血浆/红细胞/PBMCs/DBSS均采用高效液相色谱-串联质谱仪进行定量。将DBS与红细胞和血浆配对进行比较。RBC TFV-DP半衰期的中位数(四分位数范围)为17.1(15.7-20.2)天，而PBMC为4.2(3.7-5.2)天。稳态时，TFV-DP为130fmol/10(6)RBCs，而PBMCs为98fmol/10(6)。FTC-TP在大多数RBC样本中均不能定量。RBC与DBS的TFV-DP的相关系数r(2)=0.83。DBS中的TFV-DP在-20℃下稳定。对RBC/DBS中TFV-DP的模拟显示，当每周给药1-7次时，每周给药导致平均变化约19fmol/10(6)RBC和230fmol/Pick。TFV和FTC分别由y=1.4x；r(2)=0.96和y=0.8x；r(2)=0.99定义。我们得出结论，DBS提供了一种方便的测量近期(TFV/FTC)和累积(RBC中TFV-DP)药物暴露的方法，具有潜在的应用于依从性监测的潜力。
Tenofovir (TFV) disoproxil fumarate (TDF)+/- emtricitabine (FTC) are widely used for HIV treatment and chemoprophylaxis, but variable adherence may lead to suboptimal responses. Methods that quantify adherence would allow for interventions to improve treatment and prevention outcomes. Our objective was to characterize the pharmacokinetics of TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs); to extend the RBC analysis to dried blood spots (DBSs); and to model how RBC/DBS monitoring could inform recent and cumulative drug exposure/adherence. Blood samples were collected from 17 HIV-negative adults at 5 visits over a 30-day pharmacokinetics study of daily oral TDF/FTC. Dosing was discontinued on day 30 and blood was collected on days 35, 45, and 60 during the washout period. Plasma/RBCs/PBMCs/DBSs were all quantified by liquid chromatography/tandem mass spectrometry. DBSs were paired with RBCs and plasma for comparisons. The median (interquartile range) RBC TFV-DP half-life was 17.1 (15.7-20.2) versus 4.2 (3.7-5.2) days in PBMCs. At steady state, TFV-DP was 130 fmol/10(6) RBCs versus 98 fmol/10(6) PBMCs. FTC-TP was not quantifiable in most RBC samples. TFV-DP in RBCs versus DBSs yielded an r(2) = 0.83. TFV-DP in DBSs was stable at -20 degrees C. Simulations of TFV-DP in RBCs/DBSs, when dosed from one to seven times per week, demonstrated that each dose per week resulted in an average change of approximately 19 fmol/10(6) RBCs and 230 fmol/punch. TFV and FTC in plasma versus DBSs was defined by y = 1.4x; r(2) = 0.96 and y = 0.8x; r(2) = 0.99, respectively. We conclude that DBSs offer a convenient measure of recent (TFV/FTC) and cumulative (TFV-DP in RBCs) drug exposure with potential application to adherence monitoring.