Botha J H, Gray A L, Miller R
Department of Clinical and Experimental Pharmacology, University of Natal, South Africa.
J Clin Pharmacol. 1995 Oct;35(10):1020-4. doi: 10.1002/j.1552-4604.1995.tb04020.x.
To evaluate the population pharmacokinetics of valproic acid in children, 97 steady-state serum valproate concentration measurements were gathered during normal, routine, outpatient care of 52 children with epilepsy (1.2-16 years of age). Levels were obtained from patients receiving valproate monotherapy (49%) or valproate with concomitant carbamazepine (32%), phenytoin (11%), or phenobarbitone (8%). A one-compartment model was used to fit the data with the Nonlinear Mixed Effects Model (NONMEM) computer program. The final model for clearance (L/hr) was CL = [EXP (0.022WT-1.38)] X M, where EXP = the base of the natural logarithm, WT = patient weight (kg) and M = a scaling factor for concomitant medication with a value of 1 for patients on valproate monotherapy and 1.61 for those receiving concomitant carbamazepine. Although phenytoin and phenobarbitone also were expected to increase valproate clearance, this could not be demonstrated, possibly because of the small number of samples taken from patients receiving these agents. Weight-adjusted values of valproate clearance decreased with increasing age. The actual mean value of 0.021 L/hr/kg for children taking monotherapy was slightly higher than values shown in most previously published reports, whereas the mean value of 0.028 L/hr/kg for patients taking concomitant carbamazepine was similar to those found previously in children taking other antiepileptic drugs.
为评估丙戊酸在儿童中的群体药代动力学，在对52名癫痫患儿（1.2至16岁）进行正常、常规门诊护理期间收集了97次稳态血清丙戊酸盐浓度测量值。这些测量值来自接受丙戊酸单药治疗（49%）或丙戊酸与卡马西平（32%）、苯妥英（11%）或苯巴比妥（8%）联合使用的患者。使用单室模型，通过非线性混合效应模型（NONMEM）计算机程序对数据进行拟合。清除率（L/小时）的最终模型为CL = [EXP (0.022WT - 1.38)] × M，其中EXP = 自然对数的底数，WT = 患者体重（kg），M = 联合用药的比例系数，丙戊酸单药治疗患者的值为1，接受卡马西平联合治疗的患者的值为1.61。尽管预计苯妥英和苯巴比妥也会增加丙戊酸的清除率，但由于从接受这些药物治疗的患者中采集的样本数量较少，无法证实这一点。丙戊酸清除率的体重校正值随年龄增长而降低。接受单药治疗的儿童的实际平均值为0.021 L/小时/千克，略高于大多数先前发表报告中的值，而接受卡马西平联合治疗的患者的平均值为0.028 L/小时/千克，与先前接受其他抗癫痫药物治疗的儿童的值相似。
