接受富马酸替诺福韦二吡呋酯联合利迪帕韦/索磷布韦治疗的患者中替诺福韦单酯浓度升高。
Increased tenofovir monoester concentrations in patients receiving tenofovir disoproxil fumarate with ledipasvir/sofosbuvir.
机构信息
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus (AMC), Aurora, CO, USA.
Department of Medicine, School of Medicine, University of Colorado AMC, Aurora, CO, USA.
出版信息
J Antimicrob Chemother. 2019 Aug 1;74(8):2360-2364. doi: 10.1093/jac/dkz184.
BACKGROUND
Intracellular tenofovir diphosphate concentrations are markedly increased in HIV/HCV coinfected individuals receiving tenofovir disoproxil fumarate (TDF) with sofosbuvir-containing treatment. Sofosbuvir may inhibit the hydrolysis of TDF to tenofovir, resulting in increased concentrations of the disoproxil or monoester forms, which may augment cell loading. We sought to quantify tenofovir disoproxil and monoester concentrations in individuals receiving TDF with and without ledipasvir/sofosbuvir.
METHODS
HIV/HCV coinfected participants receiving TDF-based therapy were sampled pre-dose and 1 and 4 h post-dose prior to and 4 weeks after initiating ledipasvir/sofosbuvir. Tenofovir disoproxil was not detectable. Tenofovir monoester in plasma and tenofovir diphosphate in PBMC and dried blood spots (DBS) were quantified using LC-MS/MS. Geometric mean ratios (week 4 versus baseline) and 95% CIs were generated for the pharmacokinetic parameters. P values reflect paired t-tests.
RESULTS
Ten participants had complete data. At baseline, geometric mean (95% CI) tenofovir monoester plasma concentrations at 1 and 4 h post-dose were 97.4 ng/mL (33.0-287.5) and 0.74 ng/mL (0.27-2.06), respectively. With ledipasvir/sofosbuvir, tenofovir monoester concentrations at 4 h post-dose were 5.02-fold higher (95% CI 1.40-18.05; P = 0.019), but did not significantly differ at 1 h post-dose (1.72-fold higher, 95% CI 0.25-11.78; P = 0.54), possibly due to absorption variability. Tenofovir diphosphate in PBMC and DBS were increased 2.80-fold (95% CI 1.71-4.57; P = 0.001) and 7.31-fold (95% CI 4.47-11.95; P < 0.0001), respectively, after 4 weeks of ledipasvir/sofosbuvir.
CONCLUSIONS
Tenofovir monoester concentrations were increased in individuals receiving TDF with ledipasvir/sofosbuvir, consistent with inhibition of TDF hydrolysis. Additional studies are needed to determine the clinical relevance of this interaction.
背景
在接受包含索磷布韦的替诺福韦二吡呋酯（TDF）治疗的 HIV/HCV 合并感染个体中，细胞内替诺福韦二磷酸浓度显著升高。索磷布韦可能会抑制 TDF 水解为替诺福韦，导致双异丙酯或单酯形式的浓度增加，从而增加细胞负荷。我们试图定量检测接受 TDF 联合 ledipasvir/索磷布韦治疗的个体的替诺福韦双异丙酯和单酯浓度。
方法
在开始接受 ledipasvir/索磷布韦治疗前和治疗后 4 周，对接受 TDF 治疗的 HIV/HCV 合并感染参与者进行了预剂量和 1 小时及 4 小时的采样。未检测到替诺福韦双异丙酯。使用 LC-MS/MS 定量检测血浆中的替诺福韦单酯和 PBMC 及干血斑（DBS）中的替诺福韦二磷酸。生成药代动力学参数的几何均数比值（第 4 周与基线）和 95%置信区间。P 值反映配对 t 检验。
结果
有 10 名参与者的数据完整。在基线时，替诺福韦单酯在 1 小时和 4 小时后血浆浓度分别为 97.4ng/mL（33.0-287.5）和 0.74ng/mL（0.27-2.06）。接受 ledipasvir/索磷布韦治疗后，4 小时后替诺福韦单酯浓度高 5.02 倍（95%CI 1.40-18.05；P=0.019），但 1 小时后浓度没有显著差异（高 1.72 倍，95%CI 0.25-11.78；P=0.54），可能是由于吸收的变异性。PBMC 和 DBS 中的替诺福韦二磷酸分别增加了 2.80 倍（95%CI 1.71-4.57；P=0.001）和 7.31 倍（95%CI 4.47-11.95；P<0.0001）。
结论
在接受 ledipasvir/索磷布韦治疗的 TDF 患者中，替诺福韦单酯浓度升高，与 TDF 水解抑制一致。需要进一步研究来确定这种相互作用的临床意义。
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