Jen J F, Glue P, Gupta S, Zambas D, Hajian G
Department of Biostatistics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Ther Drug Monit. 2000 Oct;22(5):555-65. doi: 10.1097/00007691-200010000-00010.
The population pharmacokinetics of ribavirin were assessed in patients with chronic hepatitis C virus (HCV) infection treated with interferon alpha-2b and ribavirin in four clinical efficacy studies. The authors collected 3450 ribavirin serum concentrations from 1105 patients at different treatment weeks for inclusion in the analysis. Population factors included gender, age, body weight, serum creatinine, creatinine clearance, and previous interferon treatment history. Ribavirin apparent clearance (CL/F) was calculated from individual patients' daily doses divided by concentration values, and the influence of these factors was assessed by multiple regression. Body weight, gender, age, and serum creatinine affected CL/F. Population mean CL/F estimates were 17.9 L/h (female) and 21.5 L/h (male) assuming an age of 40 years and body weight of 70 kg. Ribavirin apparent clearance increased as a function of body weight and decreased at ages greater than 40 years. Serum creatinine had little influence on CL/F, which may reflect the relatively normal renal function of these patients. Total CL/F variability was approximately 28%. The four covariates in the model explained 27% of this variability, and were thus of limited clinical significance because of the substantial residual variability not accounted for by the model. In assessing the relationship between pharmacokinetics and pharmacodynamics, the week 4 hemoglobin nadir value was negatively associated with week 4 ribavirin concentrations. The percentage of reduction from baseline was positively associated with ribavirin concentrations, although these data were highly variable. Loss of HCV-RNA at 24 weeks after completion of treatment was considered a response to interferon and ribavirin treatment in a logistic regression analysis of clinical and pharmacokinetic variables and treatment response in the interferon-naive patients. Hepatitis C virus genotype, pretreatment HCV-RNA titer, duration of treatment period, week 4 ribavirin concentration, and patient age affected the likelihood of response. Higher ribavirin concentrations at treatment week 4 were associated with a higher response rate. Variables that have predictive value for treatment outcome in patients treated with interferon and ribavirin are similar to those previously reported for interferon monotherapy.
在四项临床疗效研究中，对接受α-2b干扰素和利巴韦林治疗的慢性丙型肝炎病毒（HCV）感染患者的利巴韦林群体药代动力学进行了评估。作者收集了1105例患者在不同治疗周的3450份利巴韦林血清浓度数据用于分析。群体因素包括性别、年龄、体重、血清肌酐、肌酐清除率以及既往干扰素治疗史。利巴韦林的表观清除率（CL/F）通过个体患者的每日剂量除以浓度值来计算，并通过多元回归评估这些因素的影响。体重、性别、年龄和血清肌酐对CL/F有影响。假设年龄为40岁、体重为70kg，群体平均CL/F估计值为女性17.9L/h，男性21.5L/h。利巴韦林的表观清除率随体重增加而升高，在年龄大于40岁时降低。血清肌酐对CL/F影响较小，这可能反映了这些患者相对正常的肾功能。CL/F的总变异性约为28%。模型中的四个协变量解释了该变异性的27%，因此由于模型未解释的大量残余变异性，其临床意义有限。在评估药代动力学与药效学之间的关系时，第4周血红蛋白最低点值与第4周利巴韦林浓度呈负相关。相对于基线的降低百分比与利巴韦林浓度呈正相关，尽管这些数据高度可变。在对初治患者的临床和药代动力学变量及治疗反应进行逻辑回归分析时，治疗完成后24周HCV-RNA的消失被视为对干扰素和利巴韦林治疗的反应。丙型肝炎病毒基因型、治疗前HCV-RNA滴度、治疗周期时长、第4周利巴韦林浓度和患者年龄影响反应的可能性。治疗第4周时较高的利巴韦林浓度与较高的反应率相关。对于接受干扰素和利巴韦林治疗的患者，具有治疗结果预测价值的变量与先前报道的干扰素单药治疗的变量相似。
