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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 a population pharmacokinetic model of valproic acid in outpatients with epilepsy and to predict the plasma concentration. Methods: One hundred and sixty-two outpatients with epilepsy were treated with sodium valproate continuously for steady state. A total of 196 blood samples were collected at the valley level. Non-linear mixed-effects model (NONMEM) was used to investigate the effects of immobilization on relative clearance of valproic acid. Results: The body building model was as follows: body weight, daily dose of sodium valproate, combination therapy and CL (L / h): CL = 0.00482 × WT + 0.110 × TAMT + 0.394 × CBZS + 0.108 × PHT + 0.0822 × PB + 0.0 583. The linear regression of the predictive value and the measured value of blood concentration in 11 patients was as follows: DV = 1.0632 × PRED-3.2 665 (μg / ml), r = 0.9663. Conclusion: The daily dose of valproic acid> 1,300mg or combination of carbamazepine, phenytoin and phenobarbital can increase the clearance rate of valproic acid, so the clinical combination therapy should pay attention to monitoring plasma concentration of valproic acid to avoid Valproate concentration is too low to cause seizures. The model established in this paper has good stability and can be used to estimate the relative clearance of valproic acid in the blood of outpatients with epilepsy and to study the drug interactions quantitatively.