NONMEM法估算中国癫痫患者苯妥英的群体药动学参数

NONMEM APPROACH FOR ESTIMATING POPULATION PHARMACOKINETIC PARAMETERS OF PHENYTOIN IN CHINESE EPILEPTICC*

临床上常规收集的１６１例门诊癫痫患者苯妥英（ＤＰＨ）的每日剂量—稳态血药浓度数据２５８对，应用ＮＯＮＭＥＭ程序一步估算其群体药动学参数（ｍｅａｎｓａｎｄ、ｖａｒｉａｎｃｅｓ），并定量地分析体重、性别、合并用药对最大消除速率Ｖｍ（ｍｇ·ｄ－１），年龄对米－曼氏常数Ｋｍ（μｇ·ｍｌ－１）的影响。异性间ＤＰＨ的Ｖｍ无显著差异，群体特征病人（体重６０ｋｇ，年龄≥１５ａ，未合并用苯巴比妥、安定或硝基安定）的Ｖｍ为４３９ｍｇ·ｄ－１，Ｋｍ为６．２１μｇ·ｍｌ－１。体重对Ｖｍ的调整值为ＷＴ／６０的０．５７次方，合并用药时Ｖｍ增加８．４ｍｇ·ｄ－１，年龄＜１５ａ则Ｋｍ下降７％。

Routine clinical pharmacok inetic data collected from epileptic out-patients whoreceived phenytoin(PHT)were analysed to estimate population pharmacokinetic parameters.Therewere 258 steady-state serum phenytoin concentrations and associated dosage (mg·d-1)from 161out-patients.The data were analysed using NONMEM program.The influence of body weight,drugcombinations and sex on the maximum elimination rate(Vm)and age on the Michaelis-Mentenconstant(Km)were investigated. The Vm and Km of phenytoin in a 60 kg adult out- patient ,without combination with other drugs(phenobarbital,clonazepam or diazepam) were estimated to be 439 mg·d-1 and 6.21μg· ml-1,respectively. The best function adjusts Vm to the 0.57 power in proportion to body weight.The Km forpatients less than 15 years old was 7%less than that for adults. The Vm of patients treated withphenytoin combined with phenobarbital ,clonazepam or diazepam will increase 8.4 mg·d-1.