丙戊酸钠的群体药代动力学

丙戊酸钠(Sodium Valproate,VPA),是目前常用的一线抗癫痫药物。作用机制与抑制电压敏感性Na^ 通道有关;抑制GABA代谢酶,使脑内GABA聚积,抑制病灶神经元过度放电,同时遏制异常放电的扩散。VPA可治疗各型癫痫,总有效率83％。其中对单纯失神性发作、全身强直-阵挛性发作(GTC)、GTC合并失神发作疗效最好,单纯部分性发作(SP)和复杂部分性     

551例癫痫患儿丙戊酸钠血药浓度监测分析

目的 探讨癫痫病患儿服用丙戊酸钠(VPA)后，其血药浓度、给药剂量及临床疗效的关系。方法 应用荧光偏振免疫法监测551例癫痫患儿服用VPA的血药浓度，结合临床疗效评价回顾性分析。结果 患儿服用VPA的有效血药浓度个体差异大。我院单一及联合应VPA治疗的总有效率为85．7％。结论 血药浓度监测结果须结合临床反应调整个体剂量，药师应重视指导患儿及家长正确使用药物。     

110例癫痫患儿丙戊酸钠血药浓度监测

目的：对丙戊酸钠治疗癫痫患者的血药浓度监测结果进行分析。方法：荧光偏振免疫法（FPIA）。结果：110例被确诊为癫痫的儿童患者血药浓度测定结果中，有47．27％的患者血药浓度在治疗 内，37．27％血药浓度偏低，15．45％血药浓度偏高。结论：儿童癫痫患者服用丙戊酸钠后的血药浓度俱本差异大，及时监测其血药浓度，实施个体化给药对控制其发作有重要意义。     

用NONMEM法建立癫痫患者丙戊酸群体药代动力学模型

目的建立丙戊酸（VPA）在癫痫患者中的群体药代动力学（PPK）模型,考察固定效应因素对VPA清除率（CL/F）的影响。方法回顾性收集贵州省人民医院111名癫痫患者VPA稳态血药浓度数据及相应的人口学、合并用药及CYP2A6基因型等资料,随机将患者分成建模组（74名）及验证组（37名）,使用建模组数据通过非线性混合效应模型（NONMEM）程序建立VPA的PPK模型。使用验证组数据来验证模型的准确度和精密度,比较基础模型和最终模型的平均预测误差（MPE）、平均绝对误差（MAE）、平均根方差（RMSE）。结果建立的最终模型包含了日用药剂量（DDO）及CYP2A6基因型,模型方程为：CL/F=0.363.DDO0.525.1.29GENECYP2A6。最终模型有更好的精密度及准确度,基础模型MPE、MAE、RMSE值为-10.631、4.40、22.55,最终模型相应值为-6.11、9.06、14.17。结论本研究初步建立癫痫患者VPA的PPK模型,VPA清除率随日给药剂量的增大而增大,CYP2A6野生型（CYP2A6＊1/＊1）组患者较CYP2A6突变型（CYP2A6＊1/＊4、CYP2A6＊4/＊4）组患者有更高的VPA清除率。     

丙戊酸钠对卡马西平药代动力学的影响

目的：考察丙戊酸钠对卡马西平药代动力学的影响。方法：6名健康志愿分别口服单剂量卡马西平片以及卡马西平和丙戊酸钠片，采用荧光偏振免疫法测定卡马西平血药浓度，经3p97程序处理，计算卡马西平的药代动力学参数以及丙戊酸钠对卡马西平药代动力学参数的影响。结果：合用丙戊酸钠后，卡马西平的Ke,CL/F明显增加，而T1/2Ke,AUC0-1明显减小（P＜0．05）。结论：丙戊酸钠可加速卡马西平的排泄，使卡马西平的半衰期缩短，生物利用度减小。     

用NONMEM法建立癫痫患者丙戊酸群体药代动力学模型

目的 建立丙戊酸(VPA)在癫痫患者中的群体药代动力学(PPK)模型,考察固定效应因素对VPA清除率(CL/F)的影响.方法 回顾性收集贵州省人民医院111名癫痫患者VPA稳态血药浓度数据及相应的人口学、合并用药及CYP2A6基因型等资料,随机将患者分成建模组(74名)及验证组(37名),使用建模组数据通过非线性混合效应模型(NONMEM)程序建立VPA的PPK模型.使用验证组数据来验证模型的准确度和精密度,比较基础模型和最终模型的平均预测误差(MPE)、平均绝对误差(MAE)、平均根方差(RMSE).结果 建立的最终模型包含了日用药剂量(DDO)及CYP2A6基因型,模型方程为:CL/F=0.363·DD00.525·1.29GENECYP2A6.最终模型有更好的精密度及准确度,基础模型MPE、MAE、RMSE值为- 10.63、14.40、22.55,最终模型相应值为-6.11、9.06、14.17.结论 本研究初步建立癫痫患者VPA的PPK模型,VPA清除率随日给药剂量的增大而增大,CYP2A6野生型(CYP2A6*1/*1)组患者较CYP2A6突变型(CYP2A6* 1/*4、CYP2A6* 4/*4)组患者有更高的VPA清除率.     

551例癫痫患儿丙戊酸钠血药浓度监测分析

目的 探讨癫痫病患儿服用丙戊酸钠(VPA)后,其血药浓度、给药剂量及临床疗效的关系。方法 应用荧光偏振免疫法监测551例癫痫患儿服用VPA的血药浓度,结合临床疗效评价回顾性分析。结果 患儿服用VPA的有效血药浓度个体差异大。我院单一及联合应VPA治疗的总有效率为85.7％。结论 血药浓度监测结果须结合临床反应调整个体剂量,药师应重视指导患儿及家长正确使用药物。     

551例癫痫患儿丙戊酸钠血药浓度监测分析

目的探讨癫痫病患儿服用丙戊酸钠(VPA)后,其血药浓度、给药剂量及临床疗效的关系.方法应用荧光偏振免疫法监测551例癫痫患儿服用VPA的血药浓度,结合临床疗效评价回顾性分析.结果患儿服用VPA的有效血药浓度个体差异大.我院单一及联合应VPA治疗的总有效率为85.7%.结论血药浓度监测结果须结合临床反应调整个体剂量,药师应重视指导患儿及家长正确使用药物.     

248例儿童丙戊酸血药浓度监测结果分析

儿童丙戊酸血药浓度监测。方法：采用荧光偏振免疫技术。结果：２８４例儿童丙戊酸血药浓度监测结果中,有效血药浓度范围占４３．４％;低有效血药浓度为４９．１９％;高于有效血药尝试为７％。其中合并苯巴比妥或卡马西平治疗３４例,有效血药浓度为１４％;低于有效血药浓度为８４％。结论：丙戊酸血药浓度因个体差异大及用药当等因素影响。ＶＰＡ血药浓度监测,在治疗儿童癫痫中具有重要的临床指导意义。     

Population pharmacokinetics of valproate in Mexican children with epilepsy

Background. The aim of this study was to determine the factors that influence valproate clearance (CL) in Mexican epileptic pediatric patients using a mixed‐effect model and sparse data of serum concentrations of valproic acid (VPA) collected during routine clinical care of patients. Methods. The number of patients included in the study was 110. The population CL was calculated by using the NONMEM program. The following covariates were tested by their influence on CL: total body weight (TBW), height, age, body surface area, daily dose (DD), sex of the patient and comedication with phenobarbital (PB) or carbamazepine. Results. The final regression model for valproic CL found best to describe the data was: CL/F=(0.0466+0.00363 TBW+0.000282 DD) ^* (1+0.236 PB). This model allows a reduction of 50% of the interindividual variability and of 31% of the residual variability described by the basic model that does not include covariables. Conclusions. Total body weight, daily dose of valproate and concomitant therapy with PB are factors that significantly influence VPA kinetic disposition and they should be considered in programming dosage regimens for this antiepileptic drug in the pediatric population. The validation of the model supports its acceptability for clinical purposes. Copyright © 2008 John Wiley & Sons, Ltd.     

Population pharmacokinetic/pharmacodynamic modeling of valproate in Chinese children with epilepsy

AIM： To establish a population pharmacokinetic/pharmacodynamic （PK/PD） model for valproate （VPA） in children with epilepsy in China, and promote reasonable use of antiepileptic drug in clinical practice. METHODS： Sparse data of VPA serum concentrations from 417 pediatric children were collected. These patients were divided into three groups： Population PK-Index group, n = 317; Population PK-Valid group, n = 100; 115 of the total 417 subjects were also included in the Population PD group. Population PK parameters of VPA were estimated based on the data from population PK-Index group. In the validation procedure, the serum concentrations of VPA from the population PK-Valid group were predicted by base and final models respectively. To assess the accuracy and precision of the predictions, mean prediction error （MPE）, mean squared prediction error （MSPE）, root mean squared prediction error （RMSPE）, weight-residues （WRES） and its 95 % confidence intervals （95 % CI） were all calculated, then compared between the two models. For population PD group, all of the ! 15 patients were VPA monotherapy. Efficacy of epilepsy treatment was divided into 5 grades according to the percentage of seizure frequency decreased （ PSFD% ）. The value of PSFD% 100%, 75% - 100%, 50% - 75%, 25% - 50%, or less than 25 % are corresponding to grade 1 to 5. For population PD group, the quantitative relationship between the VPA serum concentrations and the probability for its efficacy score was characterized by logistic regression.[第一段]     

用NONMEM法建立中国癫痫儿童丙戊酸钠的群体药动学/药效学结合模型

目的:建立中国癫痫儿童应用丙戊酸钠(VPA)的群体药动学药效学(PPKPD)结合模型,为设计个体化用药方案奠定基础。方法:回顾性收集246例癫痫患儿应用VPA的临床数据。血药浓度是常规监测的稳态浓度。用246例患儿的数据,通过NONMEM法已经自行成功建立PPK模型。现将246例中单用VPA的69例的数据与已经建立的PPK模型结合,建立PPKPD模型。药效指标用癫痫发作次数减少百分比,分为5级。应用Logistic回归分析,拟合线性药效模型,用NONMEM法建立PPKPD模型,求算血药浓度获得某一级疗效的概率。结果:应用Logistic回归分析,拟合线性药效模型,求算出血药浓度获得某一级疗效的概率:血药浓度超过23μg·ml-1时,5级的概率小于50%,获得4、3、2级的最大概率及浓度为(30μg·ml-1,32.3%)、(50μg·ml-1,26.3%)、(65μg·ml-1,36.5%);血药浓度超过78μg·ml-1时,1级的概率大于50%;浓度为100μg·ml-1时,1级的概率约84.2%。结论:用NONMEM法成功地建立了中国癫痫儿童应用VPA的PPKPD模型,定量地求出某一血药浓度获得不同疗效等级的概率。     

Population pharmacokinetics of valproate in Chinese children with epilepsy

Aim： The aim of the present study is to establish a population pharmacokinetic （PPK） model of valproate （VPA） in Chinese epileptic children to promote the reasonable use of anti-epileptic drugs. Methods： Sparse data of VPA serum concentrations from 417 epileptic children were collected. These patients were divided into 2 groups： the PPK model group （n=317） and the PPK valid group （n=100）. The PPK parameter values of VPA were calculated by NONMEM software using the data of the PPK model group. A basic model and a final model were set up. To validate the 2 models, the concentrations of PPK valid group were predicted by each model, respectively. The mean prediction error （MPE）, mean squared prediction error （MSPE）, root mean squared prediction error （RMSPE）, weight residues （WRES）, and the 95% confidence intervals （95% CI） were also calculated. Then, the values between the 2 models were compared. Results： The PPK of VPA was determined by a 1-compartment model with a first-order absorption process. The basic model was： Ka=3.09 （h^-1）, V/F=20.4 （L）, CL/F=0.296 （L/h）. The final model was： Ka=0.251＋2.24-（1-HS） （h^-l）, V/F=2.8 8＋0.157-WT （L）, CL/F=0.106^0.98.CO＋ 0.0157·AGE （L/h）. For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -23.53 （-30.36,-16.70）, 3728.96 （2872.72, 4585.20）, 39.62 （34.34, 44.90）, and-0.06 （-0.14, 0.02）, respectively. For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -1.16 （-4.85, 2.53）, 1002.83 （1050.64,1143.61）, 23.04 （21.12, 24.96）, and 0.08 （-0.04, 0.20）, respectively. The final model was more optimal than the basic model. Conclusion： The PPK model of VPA in Chinese epileptic children was successfully established. It will be valuable to facilitate individualized dosage regimens.     

Pharmacokinetics of sodium valproate in epileptic patients: Prediction of maintenance dosage by single-dose study

Summary Pharmacokinetic analysis of the plasma valproic acid concentration-time course, following a single oral dose (600 mg) of sodium valproate, was performed in 20 epileptic patients as an aid to the prediction of a proper chronic dosage regimen. A simple one-compartment model was found inadequate to describe the drug concentration-time course in 15 of the 20 patients studied. The average elimination ( phase) half-life of 9 h was shorter than that previously reported in healthy subjects. The latter observation and the wide variation in plasma valproic acid clearance observed between patients (0.09–0.53 ml/kg/min) may have been related to its altered disposition by concomitant anticonvulsant therapy. Sodium valproate maintenance therapy, determined by single-dose pharmacokinetic prediction of steady-state plasma valproic acid levels, did not require dosage adjustment because of unwanted effects. However, the occurrence of drug-related adverse events led to dosage reduction in 4 of 9 patients whose chronic therapy was not pharmacokinetically predicted. Moreover, the pharmacokinetic variability demonstrated for sodium valproate by patients on multiple therapy, whose chronic sodium valproate therapy was pharmacokinetically predicted, indicates the value of monitoring plasma valproic acid levels for the regulation of anticonvulsant therapy.     

273例癫痫患儿血清丙戊酸浓度和剂量分析

目的:研究丙戊酸钠治疗癫痫的量-效关系,为临床癫痫患儿合理应用丙戊酸钠提供参考。方法:回顾性分析我院采用荧光偏振免疫分析法测定的273例癫痫患儿血清丙戊酸浓度及其使用的丙戊酸钠剂量。结果:要达到相似的血清丙戊酸浓度,不同年龄组的癫痫患儿丙戊酸钠给药剂量有差异,1～3岁患儿所需的剂量最大。服用相似剂量不同剂型的丙戊酸钠,缓释片的平均血药浓度明显高于溶液剂和普通片剂。血清丙戊酸浓度与按体表面积计算的日剂量相关性优于按体质量计算的日剂量。结论:血清丙戊酸浓度与剂量相关性差,个体差异大,临床上在使用丙戊酸钠治疗癫痫患儿时,应监测血药浓度并实行个体化给药。     

反相高效液相色谱-柱前衍生法测定人血清中丙戊酸浓度

目的 建立人血清中丙戊酸浓度测定方法。方法 将血清酸化,用乙醚提取,以环己烷羧酸为内标,α-溴苯乙酮为衍生化试剂,采用高效液相色谱法测定。色谱柱:Eclipse Plus C₁₈柱(150 mm×4.6 mm,5 μm),流动相:甲醇-水(70:30),检测波长:248 nm,流速:1.0 ml/min。结果 血清中丙戊酸浓度线性范围为8.65~173 μg/ml,平均回收率>99.27%,日内和日间RSD<5%。结论 本法快速、简便、准确,适合于临床血药浓度监测。     

PFIA法测定450例癫痫患者丙戊酸钠的血药浓度

目的通过PFIA法(荧光偏振免疫分析法)测定丙戊酸钠的血药浓度,探讨丙戊酸钠临床上的合理应用。方法以PFIA法测定450例癫痫患者的丙戊酸钠的血药浓度。结果450例丙戊酸钠血药浓度的监测结果中,在50~100μg.mL-1治疗窗口的有266例(59.11%),<50μg.mL-1有150例(33.33%),>100μg.mL-1有34例(7.55%);丙戊酸钠治疗的总有效率为80.00%。结论丙戊酸钠的血药浓度存在个体差异大,用药期间定期监测血药浓度对提高疗效以及确保患者用药安全具有重要意义。     

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

Aim:

To establish a population pharmacokinetics (PPK) model for lamotrigine (LTG) in Chinese children with epilepsy in order to formulate an individualized dosage guideline.

Methods:

LTG steady-state plasma concentration data from therapeutic drug monitoring (TDM) were collected retrospectively from 284 patients, with a total of 404 plasma drug concentrations. LTG concentrations were determined using a HPLC method. The patients were divided into 2 groups: PPK model group (n=116) and PPK valid group (n=168). A PPK model of LTG was established with NONMEM based on the data from PPK model group according to a one-compartment model with first order absorption and elimination. To validate the basic and final model, the plasma drug concentrations of the patients in PPK model group and PPK valid group were predicted by the two models.

Results:

The final regression model for LTG was as follows: CL (L/h)=1.01^*(TBW/27.87)^0.635*e^−0.753*VPA*e^0.868*CBZ*e^0.633*PB, Vd (L)= 16.7^*(TBW/27.87). The final PPK model was demonstrated to be stable and effective in the prediction of serum LTG concentrations by an internal and external approach validation.

Conclusion:

A PPK model of LTG in Chinese children with epilepsy was successfully established with NONMEM. LTG concentrations can be predicted accurately by this model. The model may be very useful for establishing initial LTG dosage guidelines.     

人工神经网络技术预测癫痫患儿服用丙戊酸后体内药物浓度

目的利用人工神经网络技术预测癫痫患儿服用丙戊酸后体内药物浓度。方法收集200例癫痫患儿服用丙戊酸后血药浓度监测结果、身高、体重及监测当日肝肾功能等15项相关指标,根据神经网络和遗传优化反向传播算法的基本原理,构建丙戊酸血药浓度预测模型,并用该浓度预测模型进行样本预测分析。结果 50个病例样本的预测结果表明,与实际测定浓度相比,误差小于10%的有29个浓度,误差在10%～15%的有10个浓度,误差在15%～20%的有7个浓度,误差大于20%的有4个浓度。误差小于15%的比率是78%。人工神经网络预测的血药浓度和实际测定浓度之间的相关系数为0.9476。结论用人工神经网络技术预测癫痫患儿服用丙戊酸后的血药浓度是可行的;有待将其广泛应用于个体化给药设计。