中国健康志愿者口服奈必洛尔的群体药代动力学模型的建立

Establishment of population pharmacokinetics model of nebivolol in Chinese healthy volunteers

建立中国健康志愿者口服奈必洛尔的群体药代动力学模型(PPK),评价奈必洛尔临床药代动力学的显著影响因素。收集25名健康志愿者的临床资料,进行单剂量和多剂量给药试验,志愿者口服奈必洛尔5 mg后,以LC-MS/MS法测定奈必洛尔血药浓度,用非线性混合效应模型法(NONMEM)建立奈必洛尔PPK模型,并用自举法进行验证。结果表明:奈必洛尔在健康志愿者体内的药代动力学可用二房室模型描述,个体间变异符合乘法模型。奈必洛尔中央室分布容积及清除率的群体典型值分别为1.84×103L和7.68×102L/h。体重、舒张压、血尿素氮和代谢表型均对奈必洛尔的PPK参数有显著影响。自举法的验证结果与模型计算值相符。所建立的PPK模型可以较好的解释奈必洛尔药代动力学个体差异显著的原因,为奈必洛尔在中国人群中的临床合理用药提供药代动力学参考。

To establish population pharmacokinetics model of nebivolol given by oral route in Chinese healthy volunteers using nonlinear mixed effect model（NONMEM）,thus evaluating the factors that could influence clinical pharmacokinetics of nebivolol.Clinical data from 25 healthy volunteers were collected and the experiments included single-dose and multiple-dose administration.Volunteers were given 5 mg nebivolol orally and plasma concentrations of the drug were determined by LC-MS/MS.The population pharmacokinetic modeling was performed with NONMEM program and estimated by bootstrap procedure.The results showed that two-compartment model had fit for nebivolol pharmacokinetics.Inter-individual variability was described by multiplicative model.Typical values of central volume of distribution and clearance were 1.84×103 L and 7.68×102 L/h.The population pharmacokinetic parameters were mainly influenced by body weight,diastolic blood pressure,blood urea nitrogen and phenotype.The parameters estimated from nonparametric bootstrap procedure were comparable to those from NONMEM.The established population pharmacokinetics model could explain the reasons for the plasma concentration of individual variations of nebivolol,which could be used to guide clinical administration to Chinese people.