Intracellular pharmacokinetics of tenofovir diphosphate, carbovir triphosphate, and lamivudine triphosphate in patients receiving triple-nucleoside regimens
Intracellular pharmacokinetics of tenofovir diphosphate, carbovir triphosphate, and lamivudine triphosphate in patients receiving triple-nucleoside regimens
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DOI：
10.1097/01.qai.0000167155.44980.e8
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发表时间：
2005-08-01
影响因子：
3.6
通讯作者：
Kearney, BP
中科院分区：
文献类型：
--
作者：
Hawkins, T;Veikley, W;Kearney, BP
目的：评估药理学机制的潜力，以解释在含有富马酸替诺福韦酯（TDF）、阿巴卡韦（ABC）和拉米夫定（3 TC）的三核苷方案中观察到的次优病毒学应答。这是对替诺福韦二磷酸盐（TFV-DP）、卡波韦三磷酸盐（CBV-TP）和拉米夫定三磷酸盐（3 TC-TP）在三核苷方案的患者。15例接受稳定TDF + ABC+第三种核苷逆转录酶（RT）抑制剂（3 TC [n = 13]，司他夫定[n = 2]）方案的患者停用TDF或ABC，代之以非核苷RT抑制剂或蛋白酶抑制剂。外周血单核细胞收集后的最后剂量的TDF或ABC在基线和超过12至96小时，以及在第14和第28天后停止。核苷酸浓度直接使用液相色谱串联质谱法测量; ABC或TDF discontinnation后的变化将提供证据的细胞内药物interaction.Results：细胞内核苷酸浓度的持续药物不受影响时，TDF或ABC被中断。与CBV-TP或3 TC-TP相比，TFV-DP的细胞内水平表现出较小的患者间和患者内变异性。TDF停药后，TFV-DP也具有持续的细胞内水平（中位半衰期为150小时，范围：60至> 175小时）。CBV-TP浓度下降到低于检测限，在所有患者的72小时后，最后一次ABC剂量按照中位半衰期为18小时（范围：12-19小时）。结论：细胞内药物相互作用不能解释次优的病毒反应与核苷治疗方案的TDF，ABC和3 TC的患者。
Objective: To evaluate the potential for a pharmacologic mechanism to explain suboptimal virologic responses observed in a triple-nucleoside only regimen containing tenofovir disoproxil fumarate (TDF), abacavir (ABC), and lamivudine (3TC).Methods: This was a prospective evaluation of intracellular concentrations and pharmacokinetics of tenofovir diphosphate (TFV-DP), carbovir triphosphate (CBV-TP), and lamivudine triphosphate (3TC-TP) in patients on triple-nucleoside regimens. Fifteen patients on a stable TDF plus ABC plus a third nucleoside reverse transcriptase (RT) inhibitor (3TC [n = 13], stavudine [n = 2]) regimen discontinued TDF or ABC, replacing it with a nonnucleoside RT inhibitor or protease inhibitor. Peripheral blood mononuclear cells were collected after the last dose of TDF or ABC at baseline and over 12 to 96 hours as well as at days 14 and 28 after discontinuation. Nucleotide concentrations were measured directly using liquid chromatography with tandem mass spectrometry; changes after ABC or TDF discontinnation would provide evidence of an intracellular drug interaction.Results: Intracellular nucleotide concentrations of the continued drugs were unaffected when TDF or ABC was discontinued. Intracellular levels of TFV-DP exhibited less inter- and intrapatient variability than CBV-TP or 3TC-TP. TFV-DP also had persistent intracellular levels on TDF discontinuation (median half-life of 150 hours, range: 60 to > 175 hours). CBV-TP concentrations fell to below the limit of detection in all patients by 72 hours after the last ABC dose in accordance with a median half-life of 18 hours (range: 12-19 hours).Conclusions: An intracellular drug interaction does not explain the suboptimal viral response in patients treated with the nucleoside-only regimen of TDF, ABC, and 3TC.