Bioengineering Laboratory, Defence Medical and Environmental Research Institute, DSO National Laboratories, Singapore.
Ther Drug Monit. 2011 Dec;33(6):719-29. doi: 10.1097/FTD.0b013e318237a9e9.
Modafinil is a psychostimulant used to treat excessive sleepiness. The aim of this study was to develop a population pharmacokinetic model of modafinil and its major metabolites in Chinese male adults and to identify covariates that predict variability in disposition.
Eighty healthy volunteer subjects were randomized to 4 oral dose groups: 3 doses of 50 mg of modafinil, 3 doses of 100 mg of modafinil, 2 doses of 200 mg of modafinil plus 1 dose of placebo, or 3 doses of placebo (each dose given 8 hourly). Blood samples were collected up to 58 hours post-first dose for plasma concentrations of modafinil and its metabolites. Pharmacokinetic data analyses were performed using noncompartmental and compartmental approaches. The population pharmacokinetic study was conducted using the nonlinear mixed-effects model software, NONMEM, and validated using the bootstrap, crossvalidation and visual predictive check approaches.
Data were best described by a 5-compartment model: 2 compartments for modafinil (first-order absorption from gut compartment) and 1 each for modafinil acid and modafinil sulfone. A covariate analysis identified body weight as influencing volumes of the central and peripheral compartments for modafinil. All the parameters were estimated with good precision (relative standard error < 39%). The visual predictive check found that the final pharmacokinetic model adequately predicted observed concentrations of all 3 molecular species. The authors developed dosing schedules to achieve minimum trough plasma modafinil concentrations of 3 mcg/mL.
A robust population pharmacokinetic model for modafinil and its metabolites was developed for the first time. Based on this model, individualized dosing based on weight is now possible.
莫达非尼是一种用于治疗过度嗜睡的精神兴奋剂。本研究旨在建立中国人男性群体中莫达非尼及其主要代谢物的群体药代动力学模型，并确定预测药物处置变异性的协变量。
80 名健康志愿者被随机分为 4 个口服剂量组：3 个剂量的 50mg 莫达非尼、3 个剂量的 100mg 莫达非尼、2 个剂量的 200mg 莫达非尼加 1 个剂量的安慰剂或 3 个剂量的安慰剂（每次 8 小时给药）。首次给药后 58 小时内采集血样，用于检测莫达非尼及其代谢物的血浆浓度。采用非房室和房室分析方法进行药代动力学数据分析。使用非线性混合效应模型软件 NONMEM 进行群体药代动力学研究，并采用 bootstrap、交叉验证和可视化预测检查方法进行验证。
数据最佳拟合 5 房室模型：2 个房室用于莫达非尼（肠腔的一级吸收），1 个房室用于莫达非尼酸和莫达非尼砜。协变量分析确定体重影响莫达非尼的中央和外周房室体积。所有参数的估计精度均较好（相对标准差<39%）。可视化预测检查发现，最终药代动力学模型能够很好地预测所有 3 种分子的观察浓度。作者制定了给药方案，以达到莫达非尼最低谷浓度 3 mcg/mL。
首次建立了莫达非尼及其代谢物的稳健群体药代动力学模型。基于该模型，现在可以根据体重进行个体化给药。
