NONMEM法估算3种抗癫痫药对丙戊酸相对清除率的影响

Estimation of the influence of three anti-epileptic drugs on relative clearance of valproic acid with NONMEM

目的 用NONMEM法定量考察卡马西平、苯妥英、苯巴比妥对门诊癫痫患者丙戊酸 (VPA)的清除率的影响。方法 16 2例门诊癫痫患者口服丙戊酸达稳态 ,得到谷浓度数据 196点 ,用FPIA法进行检测。采用NONMEM法估算其相对清除率CL ,并定量考察体重、合并用药、丙戊酸钠剂量对清除率的影响。结果 按口服一房室开放模型得到体重、丙戊酸钠日剂量、合并用药等因素与清除率CL(L·h-1)之间的拟合模型为 :CL =0 .0 0 4 82WT +0 .110TAMT +0 .394CBZS +0 .10 8PHT +0 .0 82 2PB +0 .0 5 83。其中WT为患者的体重 (kg) ;TAMT的值当VPA剂量大于 1.3g·d-1时为 1,否则为 0 ;CBZS的值为卡马西平按体表面积折算的日剂量 (g·m-2 ·d-1) ;PHT的值当合用苯妥英钠按体表面积折算的日剂量 (mg·m-2 ·d-1) >15 0时为 1,否则为 0 ;PB的值当合用苯巴比妥按体表面积折算的日剂量 (mg·m-2 ·d-1) >4 0时为 1,否则为 0。结论 ①使用丙戊酸钠剂量 >1.3g·m-2 ·d-1或合并使用卡马西平、苯妥英钠、苯巴比妥均可使VPA的清除率增加 ;②儿童CL/WT较成人高 ,提示VPA在儿童体内更易清除。

OBJECTIVE: To estimate the influence of carbamazepine, phenytoin, phenobarbital on the relative clearance (CL) of valproic acid (VPA) in Chinese epileptic out-patients. METHODS: 196 blood samples of VPA at trough were collected from 162 epileptic out-patients, who were continually administered VPA for over 1 month. All of the samples were analyzed by FPIA. The influence of body weight, VPA daily dose and carbamazepine on CL were investigated. RESULTS: One compartment open model with first-order absorption and elimination was used to analyze the data. The influence of the fixed effects on relative clearance of VPA was investigated using Nonlinear Mixed Effect Model (NONMEM). The final regression of CL (L&middoth-1) was: CL = 0. 004 82WT + 0. 110 TAMT + 0. 394 CBZS + 0. 108 PHT + 0. 082 2 PB + 0. 058 3, where WT was total body weight (kg), TAMT = 1 for VPA daily dose > 1.3 g and 0 for others, CBZS was carbamazepine daily dose divided by body surface area (BSA), PHT = 1 for phenytoin dose>150 mg&middotm-2&middotd-1 and 0 for others, PB = 1 for phenobarbital dose>40 mg&middotm-2&middotd-1 and 0 for others. CONCLUSION: 1 The clearance of VPA was increased while highly dosed or co-administered with carbamazepine, phenytoin or phenobarbital. 2 The CL/WT of children were higher than that of adults.