Bruno R, Vivier N, Montay G, Le Liboux A, Powe L K, Delumeau J C, Rhodes G R
Department of Drug Metabolism and Pharmacokinetics, Rhône-Poulenc Rorer Research and Development, Antony, France.
Clin Pharmacol Ther. 1997 Nov;62(5):518-26. doi: 10.1016/S0009-9236(97)90047-3.
To characterize the population pharmacokinetic of riluzole in patients with amyotrophic lateral sclerosis (ALS).
One hundred patients with ALS who were participating in a multicenter phase III dose-ranging trial of riluzole were sampled on 179 visits. The sampling strategy (two samples per visit) was varied across patients to define the population kinetic profile (full screen). Riluzole plasma levels were determined by HPLC, and the data were analyzed by nonlinear mixed-effect modeling (NONMEM program) with use of a one-compartment structural model. The model incorporated interoccasion (visit-to visit) variability.
In the basic one-compartment pharmacokinetic model, interindividual variability in plasma clearance (51.4%) was higher than intraindividual (visit-to-visit) variability (28.0%), indicating uniform pharmacokinetic behavior during long-term therapy. Riluzole clearance was independent of dosage (25 to 100 mg twice daily), treatment duration (up to 10 months), age, and renal function; gender and smoking were the most important patient covariates, with hepatic function having lesser influence. Typical value of clearance was 51.4 L/hr for a nonsmoking male patient. It was 32% lower in women than in men and 36% lower in nonsmokers than in smokers. Gender- and smoking-related variations in riluzole exposure at the recommended dosage (50 mg twice daily) were within the range of exposures achieved (with no untoward effect) in this dose-ranging study.
The pharmacokinetics of riluzole has been characterized in patients during long-term therapy. Riluzole clearance is independent of dose and treatment duration. Within-patient variability is low. Gender and smoking status are the main covariates to explain interpatient variability.
描述利鲁唑在肌萎缩侧索硬化症（ALS）患者中的群体药代动力学特征。
100例参与利鲁唑多中心III期剂量范围试验的ALS患者在179次访视时进行采样。采样策略（每次访视采集两份样本）因患者而异，以确定群体动力学特征（全面筛查）。利鲁唑血浆水平通过高效液相色谱法测定，数据采用单室结构模型通过非线性混合效应建模（NONMEM程序）进行分析。该模型纳入了访视间（每次访视之间）的变异性。
在基本的单室药代动力学模型中，血浆清除率的个体间变异性（51.4%）高于个体内（每次访视之间）变异性（28.0%），表明长期治疗期间药代动力学行为具有一致性。利鲁唑清除率与剂量（每日两次25至100毫克）、治疗持续时间（长达10个月）、年龄和肾功能无关；性别和吸烟是最重要的患者协变量，肝功能的影响较小。非吸烟男性患者的清除率典型值为51.4升/小时。女性比男性低32%，非吸烟者比吸烟者低36%。在推荐剂量（每日两次50毫克）下，利鲁唑暴露的性别和吸烟相关差异在该剂量范围研究中达到的暴露范围内（无不良影响）。
已描述了利鲁唑在患者长期治疗期间的药代动力学特征。利鲁唑清除率与剂量和治疗持续时间无关。患者内变异性较低。性别和吸烟状态是解释患者间变异性的主要协变量。
