Bruchfeld Annette, Lindahl Karin, Schvarcz Robert, Ståhle Lars
Division of Renal Medicine, Department of Clinical Science, Karolinska Institute and Huddinge University Hospital, Stockholm, Sweden.
Ther Drug Monit. 2002 Dec;24(6):701-8. doi: 10.1097/00007691-200212000-00004.
A combination of interferon alfa and ribavirin is standard therapy for chronic hepatitis C virus (HCV). Ribavirin dosage is currently based on body weight. The aim of this study was to critically evaluate current dosage recommendations on the basis of a population pharmacokinetic analysis. The data consisted of 383 ribavirin plasma concentration samples collected from 63 patients undergoing treatment of HCV. Forty-four patients had normal range serum creatinine with an estimated glomerular filtration rate (GFR = estimated creatinine clearance) of 57-144 mL/min. Another 19 patients had renal impairment with a GFR of 5-57 mL/min. Population factors were age, gender, body weight, serum creatinine, and GFR. A population pharmacokinetic analysis with a two-compartment model was carried out using nonlinear mixed effect modeling. Ribavirin clearance was found to be linearly dependent on renal function with a small nonrenal clearance dependent on body weight and age. Estimated GFR was a significantly better predictor of ribavirin clearance than body weight alone. There remained a significant 40% interindividual variability in ribavirin total clearance not explained by estimated GFR and body weight. The volume of distribution was large and proportional to body weight (V = 44.3 x body weight), which resulted in a long half-life (100-500 hours, depending on GFR) and a long time to steady state (3-12 weeks). Ribavirin dosage should mainly be based on renal function and not, as currently recommended, on body weight alone. A ribavirin-dosing schedule based on GFR and body weight to reach an intended target concentration is proposed. Ribavirin monitoring may be useful for optimizing HCV treatment not only in patients with renal insufficiency but also in other patients considering the time to steady state and the interindividual variability in ribavirin clearance.
干扰素α与利巴韦林联合使用是慢性丙型肝炎病毒（HCV）的标准治疗方法。目前利巴韦林的剂量是根据体重来确定的。本研究的目的是基于群体药代动力学分析对当前的剂量推荐进行严格评估。数据包括从63例接受HCV治疗的患者中收集的383份利巴韦林血浆浓度样本。44例患者的血清肌酐在正常范围内，估计肾小球滤过率（GFR = 估计肌酐清除率）为57 - 144 mL/分钟。另外19例患者存在肾功能损害，GFR为5 - 57 mL/分钟。群体因素包括年龄、性别、体重、血清肌酐和GFR。使用非线性混合效应模型进行了二室模型的群体药代动力学分析。发现利巴韦林清除率与肾功能呈线性相关，少量非肾清除率与体重和年龄有关。估计的GFR比单独的体重更能显著预测利巴韦林清除率。利巴韦林总清除率仍有40%的显著个体间变异性无法用估计的GFR和体重来解释。分布容积很大且与体重成正比（V = 44.3×体重），这导致半衰期较长（100 - 500小时，取决于GFR）以及达到稳态的时间较长（3 - 12周）。利巴韦林剂量应主要基于肾功能，而不是像目前推荐的那样仅基于体重。提出了一种基于GFR和体重的利巴韦林给药方案以达到预期的目标浓度。考虑到达到稳态的时间和利巴韦林清除率的个体间变异性，利巴韦林监测不仅对肾功能不全患者优化HCV治疗可能有用，对其他患者也可能有用。
