Grasela T H, Fiedler-Kelly J B, Salvadori C, Marey C, Jochemsen R
Center for Pharmacoepidemiology Research, University at Buffalo, New York.
Eur J Clin Pharmacol. 1993;45(2):173-9. doi: 10.1007/BF00315502.
Two thousand three hundred and thirty five plasma concentrations of tianeptine from 112 patients enrolled in nine studies of tianeptine pharmacokinetics performed prior to the marketing of the drug were pooled for analysis using mixed-effect modeling. Studies represented a combination of single dose and multiple dosing at steady-state. Tianeptine plasma concentration time data were fit to a two compartment model with first order absorption using the NONMEM computer program. The results of this analysis suggested that alcoholism is associated with significant increase in clearance (124% increase) and volume of the central compartment (161% increase). The volume of the peripheral compartment is significantly lower in women (31% decrease) and in depressed patients (59% decrease). The population mean (interindividual variability) clearance was equal to 0.17 l.h-1 x kg-1 (28.6%), the volume of central compartment was 0.13 l.kg-1 (60.4%), intercompartmental clearance was 0.07 l.h-1 x kg-1 (30.1%), volume of the tissue compartment was 1.17 l.kg-1 (28.3%), and the absorption rate constant was 0.63 h-1 (21.8%). The residual variability was approximately 30% at concentrations expected during clinical use of the drug. Because of the increased clearance, alcoholic patients would be expected to have significantly reduced concentrations during steady-state dosing. These population parameters provide a basis for developing initial dosing recommendations and for performing bayesian evaluations of drug concentrations obtained in post-marketing studies.
对药物上市前进行的9项噻奈普汀药代动力学研究中纳入的112例患者的2335份噻奈普汀血浆浓度进行汇总，采用混合效应模型进行分析。这些研究包括单剂量给药和稳态多剂量给药。使用NONMEM计算机程序将噻奈普汀血浆浓度-时间数据拟合为具有一级吸收的二室模型。该分析结果表明，酒精中毒与清除率显著增加（增加124%）和中央室容积显著增加（增加161%）相关。外周室容积在女性中显著降低（降低31%），在抑郁症患者中显著降低（降低59%）。总体平均（个体间变异性）清除率等于0.17 l·h⁻¹·kg⁻¹（28.6%），中央室容积为0.13 l·kg⁻¹（60.4%），室间清除率为0.07 l·h⁻¹·kg⁻¹（30.1%），组织室容积为1.17 l·kg⁻¹（28.3%），吸收速率常数为0.63 h⁻¹（21.8%）。在药物临床使用预期的浓度下，残余变异性约为30%。由于清除率增加，预计酒精性患者在稳态给药期间浓度会显著降低。这些总体参数为制定初始给药建议以及对上市后研究中获得的药物浓度进行贝叶斯评估提供了基础。
