Antiviral Pharmacology Laboratory, College of Pharmacy (COP), University of Nebraska Medical Center (UNMC).
Division of Infectious Diseases, Department of Internal Medicine, College of Medicine (COM), UNMC.
AIDS. 2018 Mar 27;32(6):761-765. doi: 10.1097/QAD.0000000000001744.
The aim of the study was to compare the intraindividual plasma and intracellular peripheral blood mononuclear cell (PBMC) pharmacokinetics of tenofovir (TFV) and its intracellular metabolite, TFV-diphosphate (TFV-DP) in patients switched from a fixed-dose combination (FDC) tablet of TFV disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir (EVG)/cobicistat (COBI) to a FDC containing TFV alafenamide (TAF)/FTC/EVG/COBI.
A single-arm, prospective, nonrandomized, cross-over, pharmacokinetic study in patients receiving a TDF-containing regimen (TDF 300 mg/FTC 200 mg/EVG 150 mg/COBI 150 mg) switched to a TAF-containing FDC regimen (TAF 10 mg/FTC 200 mg/EVG 150 mg/COBI 150 mg).
Single, sparse plasma and PBMC samples were collected during TDF therapy and 4-8 weeks post-switch to the TAF-containing regimen. Plasma TFV and cell associated TFV-DP concentrations were determined with validated liquid chromatography tandem mass spectrometry methods. PBMC cell enumeration was performed by quantification of RNaseP (RPP30) gene copy numbers using a highly sensitive droplet digital PCR assay. Plasma and PBMC pharmacokinetics were summarized as geometric mean and compared as a geometric mean ratio with a Wilcoxon signed-rank test.
In 30 participants with evaluable data, TFV plasma concentrations decreased 90% [TDF: 99.98 (2.24) ng/ml vs. TAF: 10.2 (1.6) ng/ml, P < 0.001] after the switch while cell-associated TFV-DP increased 2.41-fold [TAF: 834.7 (2.49) vs. TDF: 346.85 (3.75) fmol/10 cells, P = 0.004].
Intraindividually, plasma TFV concentrations significantly decreased while cell associated TFV-DP concentrations significantly increased after switching from a TDF to a TAF-containing antiretroviral therapy regimen.
本研究旨在比较从富马酸替诺福韦二吡呋酯（TDF）/恩曲他滨（FTC）/艾维雷韦（EVG）/考比司他（COBI）固定剂量复方制剂（FDC）转换为含替诺福韦艾拉酚胺（TAF）/FTC/EVG/COBI 的 FDC 后，患者血浆和外周血单个核细胞（PBMC）中替诺福韦（TFV）及其细胞内代谢物 TFV-二磷酸（TFV-DP）的个体内药代动力学。
这是一项在接受 TDF 治疗方案（TDF 300mg/FTC 200mg/EVG 150mg/COBI 150mg）的患者中进行的单次、前瞻性、非随机、交叉、药代动力学研究，患者随后转换为含 TAF 的 FDC 方案（TAF 10mg/FTC 200mg/EVG 150mg/COBI 150mg）。
在 TDF 治疗期间和转换为含 TAF 方案后 4-8 周采集单次、稀疏的血浆和 PBMC 样本。采用经验证的液相色谱串联质谱法测定血浆 TFV 和细胞相关 TFV-DP 浓度。使用高度敏感的液滴数字 PCR 测定法定量 RNaseP（RPP30）基因拷贝数来进行 PBMC 细胞计数。总结了血浆和 PBMC 的药代动力学参数，并用 Wilcoxon 符号秩检验比较了几何均数比值。
在 30 名可评估数据的参与者中，转换后 TFV 血浆浓度下降了 90%[TDF：99.98（2.24）ng/ml 与 TAF：10.2（1.6）ng/ml，P＜0.001]，而细胞相关 TFV-DP 增加了 2.41 倍[TAF：834.7（2.49）ng/ml 与 TDF：346.85（3.75）ng/ml，P=0.004]。
个体内，从 TDF 转换为 TAF 含抗逆转录病毒治疗方案后，血浆 TFV 浓度显著下降，而细胞相关 TFV-DP 浓度显著增加。
