Yukawa E, To H, Ohdo S, Higuchi S, Aoyama T
Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Fukuoka, Japan.
Eur J Clin Pharmacol. 1998 Mar;54(1):69-74. doi: 10.1007/s002280050423.
Nonlinear mixed-effects modeling (NONMEM) was used to estimate the effects of drug drug interaction on phenobarbitone clearance values, using 648 serum levels gathered during the routine clinical care of 349 pediatric and adult epileptic patients (age range, 0.4-33.3 years). Patients received phenobarbitone as monotherapy or in combination with either of the antiepileptic drugs carbamazepine or valproic acid.
The final model describing phenobarbitone clearance was CL = 52.3 x TBW(-0.567) x CO, where CL is clearance (ml x kg(-1) x h(-1)), TBW is total body weight (kg) and CO is a scaling factor for concomitant medication with a value of 1 for patients on phenobarbitone monotherapy, 46.4(-1/TBW) for those patients receiving concomitant carbamazepine and 0.642 for those patients receiving concomitant valproic acid. Phenobarbitone CL was highest in the very young and decreased in a weight-related fashion in children, with minimal changes observed in adults. This pattern was consistent whether phenobarbitone was administered alone or coadministered with carbamazepine or valproic acid. When phenobarbitone was coadministered with carbamazepine or valproic acid, phenobarbitone CL decreased compared with that in monotherapy. Its magnitudes in the presence of carbamazepine are maximal in early childhood (about 54%) and decreased in a weight-related fashion in older children, with minimal changes observed in adults. Concomitant administration of phenobarbitone and valproic acid resulted in a 35.8% decrease of phenobarbitone CL.
采用非线性混合效应模型（NONMEM），利用在349例儿科和成人癫痫患者（年龄范围为0.4 - 33.3岁）的常规临床护理期间收集的648份血清水平数据，评估药物相互作用对苯巴比妥清除率值的影响。患者接受苯巴比妥单药治疗或与抗癫痫药物卡马西平或丙戊酸联合使用。
描述苯巴比妥清除率的最终模型为CL = 52.3×TBW（-0.567）×CO，其中CL为清除率（ml×kg（-1）×h（-1）），TBW为总体重（kg），CO是合并用药的比例因子，苯巴比妥单药治疗患者的值为1，接受卡马西平联合治疗的患者为46.4（-1/TBW），接受丙戊酸联合治疗的患者为0.642。苯巴比妥清除率在幼儿中最高，在儿童中随体重增加而降低，在成人中变化最小。无论苯巴比妥是单独给药还是与卡马西平或丙戊酸联合给药，这种模式都是一致的。当苯巴比妥与卡马西平或丙戊酸联合使用时，与单药治疗相比，苯巴比妥清除率降低。在卡马西平存在的情况下，其降低幅度在幼儿期最大（约54%），在大龄儿童中随体重增加而降低，在成人中变化最小。苯巴比妥与丙戊酸联合给药导致苯巴比妥清除率降低35.8%。
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