丙戊酸群体药动学模型的建立与临床应用

Construction and Clinical Application of the Population Pharmacokinetic Model of Valproic Acid

目的:建立门诊癫痫患者应用丙戊酸的群体药代动力学模型,并进行血药浓度预测。方法:162例门诊癫痫患者连续服用丙戊酸钠达稳态,测定其谷浓度附近血样标本共196个。用非线性混合效应模型(NONMEM)考察固定效应对丙戊酸相对清除率的影响。结果:体重、丙戊酸钠日剂量、合并用药等因素与清除率CL(L/h)之间的拟舍模型为:CL=0.00 482×WT+0.110×TAMT+0.394×CBZS+0.108×PHT+0.0822×PB+0.0 583。将11例患者血药浓度预测值与实测值作线性回归,其方程为:DV=1.0 632×PRED-3.2 665(μg/ml),r=0.9 663。结论:丙戊酸日剂量>1 300mg或合并应用卡马西平、苯妥英、苯巴比妥均可使丙戊酸的清除率增加,故临床合并用药时应注意监测丙戊酸血药浓度,避免丙戊酸浓度过低而引起癫痫发作。本文所建立的模型稳定性好,可用于估算门诊癫痫患者血液中丙戊酸的相对清除率,并可定量研究药物的相互作用。

OBJECTIVE: To establish the population pharmacokinetic model of valproic acid(VPA) and predict their serum concentrations.METHODS: 196 blood samples of VPA on steady-state trough level were collected from 162 epileptic out-patients, who have continuously taken VPA for over 1 month.The influence of the fixed effects on relative clearance of VPA was investigated using Nonlinear Mixed Effect Model(NONMEM) .RESULTS: The final regression of CL(L/ h) was: CL = 0.00482×WT+0.110×TAMT + 0.394×CBZS + 0.108×PHT+0.0822×PB + 0.0583.Other 11 VPA concentrations of the outpatients were estimated using the model as external validation.The regression between predictions(PRED) and dependant variable(DV) was: DV = 1.0 632×PRED-3.2 665(r = 0.9 663) .CONCLUSION: (1)The clearance of VPA will increase while highly dosed or co-administrated with carbamazepine, phenytoin or phenobarbital .The concentration of VPA should be monitored while co-administrated with these drugs.(2)The model showed good stability and performance,and it can be used to estimate the relative clearance of VPA and drug interactions quantitively.