Schrezenmeier Eva, Hoffmann Friederike, Jaeger Carsten, Schrezenmeier Jens, Lisec Jan, Glander Petra, Algharably Engi, Kreutz Reinhold, Budde Klemens, Duerr Michael, Halleck Fabian
Departments of Nephrology and Medical Intensive Care and.
Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin.
Ther Drug Monit. 2019 Feb;41(1):53-58. doi: 10.1097/FTD.0000000000000567.
Limited data exist on the pharmacokinetic profile of novel direct-acting antivirals in kidney transplant recipients. Daclatasvir is primarily eliminated through the biliary route and sofosbuvir through the renal route; here, we report the pharmacokinetic profile of combined treatment with these compounds in a prospective study of hepatitis C virus (HCV)-positive kidney transplant recipients (EudraCT: 2014-004551-32).
In this study, plasma samples of 16 HCV-positive kidney transplant recipients receiving daclatasvir and sofosbuvir were collected at 4 time points at days 1, 7, 14, 21, 56, and 84 after start of treatment. Inclusion criteria were stable graft function and an estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m. Daclatasvir, sofosbuvir, and GS-331007 (inactive metabolite of sofosbuvir) plasma concentrations were determined using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry.
All patients showed a rapid virological response with HCV RNA below the detection limit 21 days after the start of therapy (medium time to viral clearance). No difference of the areas under the concentration-time curve (AUC) of daclatasvir, sofosbuvir, and GS-331007 was observed between patients with an eGFR below or ≥60 mL/min. For GS-331007, no relevant changes of trough levels were observed over time. Mean GS-331007 trough levels were 339.5 ± 174.9 ng/mL in patients with an eGFR ≥60 mL/min and 404.3 ± 226 ng/mL in patients with an eGFR <60 mL/min at day 7 (P = 0.52). At day 84, GS-331007 trough levels were 357.8 ± 200.8 and 404.2 ± 70.2 ng/mL in patients with an eGFR ≥60 mL/min and in patients with an eGFR <60 mL/min, respectively (P = 0.51). The accumulation ratios of renally eliminated GS-331007 for AUC and Cmax did not significantly differ between the 2 eGFR groups at day 7.
An impaired eGFR (30-60 mL/min) does not lead to a dose accumulation of daclatasvir, sofosbuvir, and GS-331007. This study provides the rationale for future studies investigating the pharmacokinetic profile of sofosbuvir-based HCV treatment in kidney transplant recipients with an eGFR <30 mL/min.
关于新型直接作用抗病毒药物在肾移植受者中的药代动力学资料有限。达卡他韦主要通过胆汁途径消除，索磷布韦通过肾脏途径消除；在此，我们在一项丙型肝炎病毒（HCV）阳性肾移植受者的前瞻性研究（欧洲临床试验注册号：2014-004551-32）中报告了这两种化合物联合治疗的药代动力学情况。
在本研究中，于治疗开始后第1、7、14、21、56和84天的4个时间点采集了16例接受达卡他韦和索磷布韦治疗的HCV阳性肾移植受者的血浆样本。纳入标准为移植肾功能稳定且估计肾小球滤过率（eGFR）>30 mL/min/1.73 m²。使用超高效液相色谱四极杆飞行时间质谱法测定达卡他韦、索磷布韦和GS-331007（索磷布韦的无活性代谢产物）的血浆浓度。
所有患者均表现出快速病毒学应答，治疗开始后21天（病毒清除中位时间）HCV RNA低于检测限。eGFR低于或≥60 mL/min的患者之间，达卡他韦、索磷布韦和GS-331007的浓度-时间曲线下面积（AUC）无差异。对于GS-331007，随时间未观察到谷浓度的相关变化。在第7天，eGFR≥60 mL/min的患者中GS-331007平均谷浓度为339.5±174.9 ng/mL，eGFR<60 mL/min的患者中为404.3±226 ng/mL（P = 0.52）。在第84天，eGFR≥60 mL/min和eGFR<60 mL/min的患者中GS-331007谷浓度分别为357.8±200.8 ng/mL和404.2±70.2 ng/mL（P = 0.51）。在第7天，两个eGFR组之间经肾脏消除的GS-331007的AUC和Cmax累积比值无显著差异。
eGFR受损（30 - 60 mL/min）不会导致达卡他韦、索磷布韦和GS-331007的剂量累积。本研究为未来研究eGFR<30 mL/min的肾移植受者中基于索磷布韦的HCV治疗的药代动力学情况提供了理论依据。
