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首页> 外文期刊>AIDS Research and Human Retroviruses >Single dose pharmacokinetics of oral tenofovir in plasma, peripheral blood mononuclear cells, colonic tissue, and vaginal tissue
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Single dose pharmacokinetics of oral tenofovir in plasma, peripheral blood mononuclear cells, colonic tissue, and vaginal tissue

机译：口服替诺福韦在血浆，外周血单核细胞，结肠组织和阴道组织中的单剂量药代动力学

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HIV seroconversion outcomes in preexposure prophylaxis (PrEP) trials of oral tenofovir (TFV)-containing regimens are highly sensitive to drug concentration, yet less-than-daily dosing regimens are under study. Description of TFV and its active moiety, TFV diphosphate (TFV-DP), in blood, vaginal tissue, and colon tissue may guide the design and interpretation of PrEP clinical trials. Six healthy women were administered a single oral dose of 300 mg tenofovir disoproxil fumarate (TDF) and 4.3 mg (12.31 MBq, 333 μCi) 14C-TDF slurry. Blood was collected every 4 h for the first 24 h, then at 4, 8, 11, and 15 days postdosing. Colonic and vaginal samples (tissue, total and CD4+ cells, luminal fluid and cells) were collected 1, 8 and 15 days postdose. Samples were analyzed for TFV and TFV-DP. Plasma TFV demonstrated triphasic decay with terminal elimination half-life median [interquartile range (IQR)] 69 h (58-77). Peripheral blood mononuclear cell (PBMC) TFV-DP demonstrated biphasic peaks (median 12 h and 96 h) followed by a terminal 48 h (38-76) half-life; Cmax was 20 fmol/million cells (2-63). One day postdose, the TFV-DP paired colon:vaginal tissue concentration ratio was 1 or greater in all subjects' tissue homogenates, median 124 (range 1-281), but was not sustained. The ratio was lower and more variable in cells extracted from tissue. Among all sample types, TFV and TFV-DP half-life ranged from 23 to 139 h. PBMC TFV-DP rose slowly in the hours after dosing indicating that success with exposure-driven dosing regimens may be sensitive to timing of the dose prior to exposure. Colonic tissue homogenate TFV-DP concentrations were greater than in vaginal homogenate at 24 h, but not in cells extracted from tissue. These and the other pharmacokinetic findings will guide the interpretation and design of future PrEP trials.
机译：口服替诺福韦（TFV）方案的暴露前预防（PrEP）试验中的HIV血清转换结果对药物浓度高度敏感，但正在研究少于每日剂量的方案。血液，阴道组织和结肠组织中TFV及其活性部分TFV二磷酸（TFV-DP）的描述可指导PrEP临床试验的设计和解释。六名健康女性单次口服300毫克富马酸替诺福韦酯（TDF）和4.3毫克（12.31 MBq，333μCi）14C-TDF浆液。在给药后的头24小时，每4小时收集一次血液，然后在给药后4、8、11和15天收集血液。给药后1、8和15天收集结肠和阴道样品（组织，总和CD4 +细胞，腔液和细胞）。分析样品的TFV和TFV-DP。血浆TFV表现出三态衰减，终末消除半衰期中值[四分位间距（IQR）] 69 h（58-77）。外周血单核细胞（PBMC）TFV-DP表现出双相峰（中值分别为12 h和96 h），其后半衰期为48 h（38-76）。 Cmax为20 fmol /百万细胞（2-63）。给药后一天，在所有受试者的组织匀浆中，TFV-DP配对的结肠：阴道组织浓度比为1或更高，中位数124（范围1-281），但没有持续。从组织中提取的细胞中，该比率较低且变化较大。在所有样品类型中，TFV和TFV-DP半衰期为23至139小时。 PBMC TFV-DP在给药后数小时内缓慢上升，表明暴露驱动的给药方案的成功可能对暴露前剂量的定时敏感。结肠组织匀浆TFV-DP浓度在24 h高于阴道匀浆，但从组织提取的细胞中则没有。这些和其他药代动力学研究结果将指导未来PrEP试验的解释和设计。

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