Decreased tacrolimus concentration following a temporal increase during interferon‐free therapy with asunaprevir and daclatasvir in patients with recurrent hepatitis C after liver transplantation
Decreased tacrolimus concentration following a temporal increase during interferon‐free therapy with asunaprevir and daclatasvir in patients with recurrent hepatitis C after liver transplantation
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肝移植后复发性丙型肝炎患者使用阿舒瑞韦和达拉他韦进行无干扰素治疗期间，他克莫司浓度暂时升高后浓度降低
DOI：
10.1111/tri.12653
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发表时间：
2016
影响因子：
3.1
通讯作者：
S. Uemoto
中科院分区：
文献类型：
--
作者：
Y. Ueda;S. Uemoto
药物相互作用（DDI）是在移植受者中使用直接作用抗病毒药物（DAA）时需要考虑的一个重要问题，因为大多数DAA是细胞色素P450 3A4的底物，细胞色素P450 3A4是一种负责他克莫司代谢的酶。自2014年11月以来，我们使用NS3/4A抑制剂asunaprevir和NS5A抑制剂daclatasvir对基因型1b丙型肝炎病毒（HCV）的移植受者进行无干扰素治疗。阿舒那匹韦和达卡他韦与他克莫司联合治疗的DDI在很大程度上是未知的。在我们的机构中，开始无干扰素方案的患者通过治疗药物监测（TDM）调整他克莫司的剂量。在这项研究中，我们评估了10例无干扰素治疗期间他克莫司浓度/剂量（C/D）比的变化，在前2周每周至少测量3次他克莫司血药浓度，此后每月测量2次。10例患者中有6例为男性，中位年龄为63岁（范围：43 - 67岁）。肝移植后至开始治疗的中位时间为122个月（2 - 153个月）。3例患者为初治患者，3例患者接受聚乙二醇干扰素加利巴韦林治疗，4例患者在肝移植后接受西米匹韦、聚乙二醇干扰素和利巴韦林三联治疗。治疗前，肝活检确定的METAVIR纤维化评分分别为F1、F2和F4的患者分别为3、6和1例。除他克莫司外，分别有7例和2例患者使用了吗替麦考酚酯和泼尼松龙。治疗前中位血清HCV-RNA载量为7.0 logIU/ml（5.9 - 7.9 logIU/ml）。中位血清肌酐水平为0.93 mg/dl（0.68 - 1.41 mg/dl）。典型病例中他克莫司血药浓度的时程如图1a所示。一名64岁的女性在肝移植后11年接受了asunaprevir（200 mg/天）和daclatasvir（60 mg/天）。他克莫司的浓度在第一周升高，但此后下降，需要增加他克莫司的剂量。10例患者中有8例在第一周他克莫司的中位C/D比值升高;与开始无干扰素治疗前的最后3个C/D比值相比，4例患者的C/D比值显著升高。与第一周的C/D比相比，在10例病例中的6例中观察到治疗后2 - 6周的C/D比显著降低，并且这些降低需要在5例患者中与治疗前相比增加他克莫司的剂量。使用TDM，在本研究期间未发生排斥反应或感染事件。图1b显示了10例病例中阿那匹韦和达卡他韦给药前、给药后第1周和给药后2 - 6周他克莫司的中位C/D比值。阿舒那匹韦和达卡他韦给药后第1周，中位C/D比值从给药前的3.95 ng/mL/mg显著增加至5.2 ng/mL/mg，但给药2周后显著降低至2.975 ng/mL/mg。治疗7天后，血清HCV-RNA水平迅速下降2.5 - 5.5 log10，5例患者在6周内无法检测到;然而，3例患者的HCV-RNA水平随后再次升高（图1c）。血清丙氨酸氨基转移酶水平在第7天显著降低，并在第6周维持在低水平（图1c）。治疗6周后血清白蛋白水平显著升高，表明阿舒那匹韦和达卡他韦给药后肝功能改善（图1c）。这项研究的结果揭示了接受阿那匹韦和达卡他韦无干扰素治疗的移植受者中他克莫司浓度的动态变化。在第一周，C/D比值的升高被认为是由DAA与他克莫司的DDI引起的。值得注意的是，无干扰素治疗1周后C/D比值显著降低。抗HCV治疗期间钙调磷酸酶抑制剂浓度的降低在接受含干扰素治疗的移植受者中也有类似报道
Drug–drug interactions (DDIs) are an important issue to consider when using direct-acting antivirals (DAAs) in transplant recipients, as most DAAs are substrates of cytochrome P450 3A4, an enzyme responsible for the metabolism of tacrolimus. Since November 2014, we have administered interferon-free therapy using the NS3/4A inhibitor asunaprevir and NS5A inhibitor daclatasvir for transplant recipients with genotype 1b hepatitis C virus (HCV). The DDIs of combination treatment using asunaprevir and daclatasvir with tacrolimus are largely unknown. In our institution, patients who start interferonfree regimen have their dose of tacrolimus adjusted by therapeutic drug monitoring (TDM). In this study, we evaluated the changes in the concentration/dose (C/D) ratio of tacrolimus during this interferon-free therapy in 10 cases, by measuring the blood concentration of tacrolimus at least three times a week in the first 2 weeks and twice a month thereafter. Six of the 10 patients were men, and the median age was 63 years (range, 43–67 years). The median time to treatment initiation after liver transplantation was 122 months (2–153 months). Three patients were treatment-na€ıve, three had peginterferon plus ribavirin therapy, and four had triple therapy with simeprevir, peginterferon, and ribavirin after the liver transplantation. Before the treatment, 3, 6, and 1 patients had METAVIR fibrosis scores of F1, F2, and F4, respectively, as determined by liver biopsy. In addition to tacrolimus, mycophenolate mofetil and prednisolone were used in 7 and 2 patients, respectively. The median serum HCV-RNA load before treatment was 7.0 logIU/ml (5.9–7.9 logIU/ml). The median serum creatinine level was 0.93 mg/dl (0.68–1.41 mg/dl). The time course of the blood concentration of tacrolimus in a typical case is shown in Figure 1a. A 64-year-old woman received asunaprevir (200 mg/day) and daclatasvir (60 mg/day) 11 years after liver transplantation. The concentrations of tacrolimus were elevated in the first week but decreased thereafter, necessitating an increase in the dose of tacrolimus. The median C/D ratio of tacrolimus in the first week was elevated in eight of the 10 patients; compared to the last three C/D ratios before the initiation of the interferon-free treatment, the C/D ratio was significantly increased in four patients. Significant decreases in the C/D ratio 2–6 weeks after treatment compared to the C/D ratio in the first week were observed in six of 10 cases, and these decreases necessitated dose increases of tacrolimus compared to before treatment in five patients. Using TDM, neither rejection nor infection episodes occurred in this study period. The median C/D ratios of tacrolimus before, in the first week after, and 2–6 weeks after asunaprevir and daclatasvir administration in the 10 cases are shown in Figure 1b. The median C/D ratio significantly increased from 3.95 ng/mL per mg before to 5.2 ng/mL per mg in the first week after asunaprevir and daclatasvir administration, but significantly decreased to 2.975 ng/ml per mg after 2 weeks of administration. Serum HCV-RNA levels rapidly decreased by 2.5–5.5 log10 after 7 days of treatment and became undetectable within 6 weeks in five patients; however, HCV-RNA levels in three patients then increased again (Figure 1c). Serum alanine aminotransferase levels significantly decreased at day 7 and were maintained at low levels at 6 weeks (Figure 1c). Serum albumin levels were significantly increased after 6 weeks of treatment, suggesting that liver function improved with asunaprevir and daclatasvir administration (Figure 1c). The findings of this study revealed the dynamic changes in tacrolimus concentration in transplant recipients undergoing interferon-free therapy with asunaprevir and daclatasvir. During the first week, the elevation of the C/D ratio was considered to be caused by the DDIs of the DAAs with tacrolimus. Notably, the C/D ratio was significantly decreased after 1 week of interferon-free therapy. A decrease in the concentration of calcineurin inhibitors during anti-HCV therapy has similarly been reported in transplant recipients treated with interferon-containing therapy