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.     

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.     

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.     

Single-dose pharmacokinetics of levetiracetam in healthy Chinese male subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Levetiracetam has been evaluated for epilepsy since 1992. * Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. * Although this antiepileptic has been well studied in Western countries, this paper describes the first such trial of the drug in a Chinese population. WHAT THIS STUDY ADDS: * Information is given on the pharmacokinetics, dose proportionality, safety and tolerability profile of levetiracetam in healthy male Chinese volunteers, and the results are compared with published data obtained in White subjects. * The pharmacokinetics and the pattern of adverse events of levetiracetam in Chinese subjects are similar to the data reported in White subjects. AIMS: The main aims of this study were to evaluate the pharmacokinetics of levetiracetam in healthy male Chinese volunteers and to assess the dose proportionality between the 500-mg and 1500-mg single doses. METHODS: This was a randomized, single-centre, single-dose, two-way crossover study. Twenty-six healthy male Chinese subjects were enrolled. All subjects received a single dose of 500 mg or 1500 mg levetiracetam tablet(s) on the dosing day, and the wash-out period was 7 days. Blood was obtained for a 36-h pharmacokinetic evaluation. RESULTS: Following single-dose administration of 500 mg and 1500 mg of levetiracetam, the median t(max) was 0.5 and 0.5 h; t(1/2) was 7.3 +/- 0.8 and 7.3 +/- 0.7 h; C(max) was 13.6 +/- 3.2 and 47.1 +/- 12.1 microg ml(-1); AUC(0-infinity) was 109.3 +/- 14.1 and 340.4 +/- 50.6 microg h(-1) ml(-1); and AUC(0-t) was 105.7 +/- 13.3 and 329.0 +/- 47.9 microg h(-1) ml(-1), respectively. CONCLUSIONS: Both C(max) and AUCs were dose-proportional over the range of 500-1500 mg. The pharmacokinetic data obtained in these Chinese subjects were similar to the historical data from a matched group of White subjects.     

左乙拉西坦对癫痫患儿骨代谢影响的临床观察

目的:探讨抗癫痫药左乙拉西坦(LEV)对癫痫患儿骨代谢的影响。方法:选择2008年1月—2010年2月期间在唐山市妇幼保健院首发初诊的原发性癫痫患儿30例,予口服LEV治疗。于治疗前和治疗后6个月、12个月分别测定骨密度(BMD)、骨碱性磷酸酶(BAP)、血钙(Ca2+)、血磷(P)、血中碱性磷酸酶(ALP)。对照组为30例未治疗的原发性癫痫患儿,同期检测上述指标。对上述骨代谢指标进行评价。结果:左乙拉西坦治疗前后骨代谢指标差异无显著性(P>0.05)。左乙拉西坦治疗前、治疗后6个月、12个月BMD、BAP、Ca、P、ALP与对照组比较差异无显著性(P>0.05)。结论:短期服用左乙拉西坦(LEV)对癫痫患儿骨代谢无明显影响。     

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]     

妊娠期癫痫患者左乙拉西坦药动学行为变化

目的：系统研究左乙拉西坦（levetiracetam,LEV）在妊娠期癫痫患者体内药动学行为变化,并探究基于LEV血药浓度监测,调整妊娠期癫痫患者的给药方案。方法：回顾性收集2017年1月至2021年7月于中国医科大学附属盛京医院就诊并进行LEV血药浓度监测的妊娠期癫痫患者的临床病历资料,计算孕前至产后LEV的表观清除率（CL）,分析妊娠期癫痫患者LEV的给药方案,并探究妊娠期合并用药对LEV体内药动学行为的影响。结果：对17例单用LEV治疗的妊娠期癫痫患者138次血药浓度监测数据的回顾性分析表明,妊娠期LEV的CL显著增加,与孕前基线相比,在妊娠早期、中期及晚期分别增加了86.39%（P<0.01）、148.30%（P<0.01）和134.69%（P<0.01）,分娩后迅速下降,于产后6周左右恢复至孕前水平。不同妊娠时期LEV给药剂量存在差异,妊娠中、晚期给药剂量较孕前分别增加了44.93%（P<0.01）和96.07%（P<0.01）。妊娠期合用具酶诱导作用的抗癫痫药能够诱导LEV代谢,使LEV的CL增加。结论：妊娠期癫痫患者LEV体内药动学行为变化显著,其CL于妊娠中期达到峰值,分娩后迅速降低。与具酶诱导作用的抗癫痫药合用会增加LEV的CL。定期监测LEV血药浓度可为妊娠期癫痫患者的药物治疗管理提供指导。     

Population pharmacokinetics of phenytoin in Singapore Chinese

Summary The pharmacokinetics of phenytoin was studied in 66 epileptic Chinese children and adults. The data were analysed by the population approach, using the non-linear mixed effect model, in the MULTI (ELS) program. There was no age or gender-related effect on either the apparent maximum elimination rate (k_max) or Michaelis-Menten constant (K_M). K_max was related to body weight 0.656. The population pharmacokinetics was similar in children and adults. K_max and K_M were estimated to be 30.72 mg·kg^–0.656 day^–1 and 2.307 mg·l^–1, respectively. K_max was higher than reported values, and K_M was comparable to that reported in a study in Japanese, but was much lower than that reported in studies of European patients. The inter-individual variability of K_M (CV 65.58%) was substantially higher than that of k_max (CV 28.49%), and the residual (intra-individual) variability was found 21.33% (CV).     

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。     

拉莫三嗪联合左乙拉西坦治疗小儿难治性癫痫的临床研究

目的 探讨拉莫三嗪与左乙拉西坦联合治疗小儿难治性癫痫的疗效及对患儿血清高迁移率族蛋白1（HMGB1）、神经节苷脂抗体（GM1-A）的影响。方法 回顾性选择2017年6月—2020年6月在昆明市儿童医院治疗的难治性癫痫患儿120例为研究对象,根据患儿的治疗方案分为对照组和试验组。对照组给予左乙拉西坦片治疗,初始剂量为10～20 mg·kg^-1·d^-1,每周增加5～10 mg·kg^-1·d^-1,增加剂量至20～40 mg·kg^-1·d^-1,加量期3～7周,连续治疗6个月。试验组在对照组基础上给予拉莫三嗪片治疗,初始剂量为0.3～0.6 mg·kg^-1·d^-1,12 h服药1次,每周加量0.3～0.6 mg·kg^-1·d^-1,目标剂量5～10 mg·kg^-1·d^-1,治疗6个月。观察两组患者的治疗效果,比较治疗前及治疗6个月后两组患儿认知功能、血清炎症因子水平、血清免疫球蛋白水平、血清HMGB1、GM1-A、神经元特异性烯醇化酶（NSE）、神经肽Y（NPY）水平。记录治疗期间患儿不良反应发生情况。结果 试验组总有效率（88.33%）显著高于对照组总有效率（70%）,两组比较差异有统计学意义（P<0.05）;治疗前两组患儿的言语智商、操作智商评分比较差异无统计学意义（P>0.05）,治疗后两组患儿的言语智商、操作智商评分均显著升高（P<0.05）,且试验组升高更显著（P<0.05）;治疗前两组患儿的免疫球蛋白A（IgA）、免疫球蛋白M（IgM）、免疫球蛋白G（IgG）水平比较差异无统计学意义（P>0.05）,治疗后两组患者的IgA、IgM、IgG水平均显著升高（P<0.05）,且试验组升高更显著（P<0.05）;治疗前两组患儿的GM1-A、NSE、NPY水平比较差异无统计学意义（P>0.05）,治疗后两组患儿的GM1-A、NSE水平均显著下降（P<0.05）,NPY水平均显著升高（P<0.05）,且试验组改善更显著（P<0.05）;治疗前两组患儿的HMGB-1、肿瘤坏死因子-α（TNF-α）、超敏C反应蛋白（hs-CRP）、白细胞介素-6（IL-6）水平比较差异无统计学意义（P>0.05）,治疗后两组患儿的HMGB-1、TNF-α、hs-CRP、IL-6水平均显著下降（P<0.05）,且试验组下降更显著（P<0.05）;两组患儿的不良反应发生率比较,差异无统计学意义（P>0.05）。结论 拉莫三嗪联合左乙拉西坦治疗难治性癫痫的治疗效果较好,可改善患儿的认知功能和免疫功能,降低炎症反应,改善HMGB-1、GM1-A水平,并且安全性较好。     

应用NLME程序建立丙戊酸在中国癫痫患儿中的群体药动学模型

目的:建立中国癫痫患儿口服丙戊酸的群体药动学模型,促进合理用药。方法:收集472例癫痫患儿口服丙戊酸后的血药浓度数据和临床资料。将患儿随机分成2组,PPK模型组(n=354):应用NLME程序建立一房室群体药动学模型(个体间变异采用指数模型,残差变异采用加法模型表示),考察各协变量对参数K_a、V_d和Cl的影响。用拟合优度、自举验证、直观预测检验(VPC)对最终模型的性能进行内部验证。PPK验证组(n=118):用最终模型预测验证组患儿的血药浓度,与实测值比较计算平均预测误差(MPE)、平均绝对预测误差(MAE)、平均预测误差平方(MSE)和均方根预测误差(RMSE)对最终模型进行外部验证。结果:PPK最终模型为:K_a=1.18×e^ηKa h^-1; V_d=0.30×e^ηVd L·kg^-1; Cl=0.008×(WT/18)^-0.92×e^ηCl L·kg^-1·h^-1。体质量负相关影响Cl。拟合优度、自举验证和VPC的评价结果表明最终模型稳定、预测结果可靠。外部验证最终模型结果为:MPE=-0.09 mg·L^-1,MAE=0.72 mg·L^-1,MSE=0.76(mg·L^-1)²,RMSE=0.87 mg·L^-1。血药浓度实测值和最终模型的个体预测值(DV vs IPRED)的决定系数R²=0.998 1。外部验证说明最终模型预测准确度高。结论:本研究成功建立了中国癫痫患儿口服丙戊酸后的群体药动学模型。模型结构表明丙戊酸体重校正的清除率随患儿年龄和体质量的增加有下降趋势。     

Population pharmacokinetics of amphotericin B in children with malignant diseases

AIMS: To construct a population pharmacokinetic model for the antifungal agent, amphotericin B (AmB), in children with malignant diseases. METHODS: A two compartment population pharmacokinetic model for AmB was developed using concentration-time data from 57 children aged between 9 months and 16 years who had received 1 mg kg(-1) day(-1) doses in either dextrose (doseform=1) or lipid emulsion (doseform=2). P-Pharm (version 1.5) was used to estimate the basic population parameters, to identify covariates with significant relationships with the pharmacokinetic parameters and to construct a Covariate model. The predictive performance of the Covariate model was assessed in an independent group of 26 children (the validation group). RESULTS: The Covariate model had population mean estimates for clearance (CL), volume of distribution into the central compartment (V) and the distributional rate constants (k12 and k21) of 0.88 l h(-1), 9.97 l, 0.27 h(-1) and 0.16 h(-1), respectively, and the intersubject variability of these parameters was 19%, 49%, 55% and 48%, respectively. The following covariate relationships were identified: CL (l h(-1)) = 0.053 + 0.0456 weight (0.75) (kg) + 0.242 doseform and V (l) = 7.11 + 0.107 weight (kg). Our Covariate model provided unbiased and precise predictions of AmB concentrations in the validation group of children: the mean prediction error was 0.0089 mg l(-1) (95% confidence interval: -0.0075, 0.0252 mg l(-1)) and the root mean square prediction error was 0.1245 mg l(-1) (95% confidence interval: 0.1131, 0.1349 mg l(-1)). CONCLUSIONS: A valid population pharmacokinetic model for AmB has been developed and may now be used in conjunction with AmB toxicity and efficacy data to develop dosing guidelines for safe and effective AmB therapy in children with malignancy.     

用群体药代动力学预测癫痫儿童丙戊酸钠血药浓度

目的 用群体药代动力(PPK)模型和贝叶斯法预测血药浓度。方法 用癫痫儿童丙戊酸钠PPK模型和USC~*PACK软件中的贝叶斯程序,对100例新癫痫患儿丙戊酸钠的血药浓度进行预测。将预测值与实测值做配对t检验,相关和回归分析,计算平均预测误差、预测误差的百分比、不同预测误差百分比的符合率及其95％可信区间、构成比和评价预测的准确程度。结果 预测值与实测值的相关系数为0.99,P<0.001,线性回归Y_(OBS)=0.99)Y_(PRED),决定系数为0.98,P<0.001;平均预测误差为-0.43μg·mL~(-1),预测误差百分比分别为5％,10％,15％,20％,25％,30％的符合率为62％,74％,82％,85％,89％,93％。结论 PPK模型和贝叶斯法可准确预测丙戊酸钠稳态血药浓度。     

Population pharmacokinetics of high-dose methotrexate in Chinese pediatric patients with medulloblastoma

Methotrexate (MTX) pharmacokinetics has substantial inter-individual variability and toxicity. In children with medulloblastoma treated with high-dose methotrexate (HD-MTX), the pharmacokinetic properties of methotrexate have not been established. A total of 660 serum samples from 105 pediatric patients with medulloblastoma were included in a population pharmacokinetic (PPK) analysis of methotrexate by using the nonlinear mixed-effects modeling method. The basic one-compartment population pharmacokinetic model was established by NONMEM software and the first-order conditional estimation (FOCE) method, and the final covariate model was obtained by the stepwise regression method. Weight (WT), creatinine clearance (CrCL), and whether the treatment was combined with dexamethasone (DEX) were covariates that had significant effects on the clearance rate (CL) of the model. The pharmacokinetic equation of CL in the final covariate model was as follows: CL_i = 9.23× (1 + 0.0005× (θ_CrCL-105.78)) × (1 + 0.0017× (θ_WT-16)) × e^ηcl,i (L/h), IF (θ_DEX) CL_i = 1.19× CL_i (L/h). The estimation accuracy of all pharmacokinetic parameters were acceptable (relative standard error < 14.74%). The goodness-of-fit diagram and bootstrap tests indicated that the final PPK model was stable with acceptable predictive ability. The PPK model may be useful for determining personalized medication levels in pediatric medulloblastoma patients undergoing HD-MTX therapy.     

丙戊酸钠、奥卡西平与左乙拉西坦分别治疗小儿癫痫的疗效及对认知功能的影响

目的 探讨丙戊酸钠、奥卡西平与左乙拉西坦分别治疗小儿癫痫的疗效及对小儿认知功能的影响。方法 收取2011年4月—2016年1月于渭南市妇幼保健院进行治疗的癫痫患儿96例作为研究对象,根据随机数字表法将其分为A、B、C组,每组各32例,分别使用丙戊酸钠、奥卡西平或左乙拉西坦进行治疗,3组患儿均治疗16周。对3组患儿临床疗效、脑电变化情况、认知功能变化情况以及用药安全性进行观察与比较。结果 A、B、C组治疗总有效率分别为71.88%、78.13%、90.63%,C组高于A、B组,但三组间比较无统计学差异。随治疗时间延长,3组患儿痫样放电好转率逐渐升高。C组好转率高于B组更高于A组,组间比较差异均有统计学意义（P＜0.05）。3组患儿治疗前语言智商（VIQ）、操作智商（PIQ）及总智商（FIQ）均无显著差异,治疗后B、C两组均较治疗前得分显著升高,且高于同期A组得分,差异有统计学意义（P＜0.05）。A组不良反应发生率为28.13%,B组为12.50%,C组为3.13%,3组间比较差异显著（P＜0.05）。结论 丙戊酸钠、奥卡西平与左乙拉西坦单药治疗小儿癫痫疗效相当,但奥卡西平与左乙拉西坦对脑电功能及小儿认知功能改善具有更加积极的意义,且以左乙拉西坦的安全性更高,具有更好的应用价值。     

Population pharmacokinetics of lamotrigine monotherapy in patients with epilepsy: retrospective analysis of routine monitoring data

Aims To examine the population pharmacokinetics of lamotrigine in patients newly diagnosed with epilepsy and receiving oral lamotrigine monotherapy for up to 48 weeks.
Methods The population consisted of 158 Caucasians and 5 Asians of whom 81 were males and 82 females. Age and weight ranged between 14 and 76 years and 41–107  kg, respectively. A one-compartment compartment model with first-order absorption and elimination was fitted to plasma lamotrigine concentration-time profiles from retrospective drug monitoring, using non-linear mixed effect modelling (NONMEM), with first-order estimation. Oral clearance (CL_o ), apparent volume of distribution ( V  / F ) and absorption rate constant ( K _a ) were the main pharmacokinetic parameters.
Results CL_o was not significantly influenced by body weight, age, gender, oral contraceptives and dose. However, due to auto-induction CL_o increased by 17.3% during the 48 weeks of therapy, from 1.94 to 2.28  l h⁻¹, and was 28.7% lower in Asians than Caucasian. The final magnitude in interpatient variability was 32%. The effect of the covariates weight, age, race and gender on V  / F was examined and none was statistically significant. The final population estimate of V  / F was 77.4  l with an interpatient variability of 34%.
Conclusions In view of the wide therapeutic margin of lamotrigine and the 21% residual variability in plasma concentrations, the modest significant effects of race and auto-induction on clearance are unlikely to be clinically significant and, thus, no dosage adjustment is warranted for these effects.     

Clinical pharmacology of levetiracetam for the treatment of epilepsy

Levetiracetam is an antiepileptic drug that is mainly indicated for the adjunctive treatment of partial-onset seizures in adults and children and of myoclonic and primary generalized tonic–clonic seizures in patients with idiopathic generalized epilepsy. In Europe, levetiracetam is also indicated as monotherapy for partial-onset seizures in patients with newly diagnosed epilepsy. Synaptic vesicle protein 2A is the primary molecular target for its anticonvulsive effect but additional mechanisms may also contribute. Recent clinical and pharmacokinetic developments for levetiracetam are reviewed in specific populations, including the effects of age, pregnancy, birth and lactation, pediatric development, and ethnic origin. The population pharmacokinetics of levetiracetam and drug–drug interactions have been explored across large adult and pediatric populations. The exposure–response relationship has also been characterized in adults and children through nonlinear mixed-effects modeling. Finally, new formulations including intravenous infusion and extended-release once-daily tablets have been compared with immediate-release tablets and oral solution, and can be used interchangeably.     

Population pharmacokinetics of pyrimethamine and sulfadoxine in children with congenital toxoplasmosis

AIMS: To develop a population pharmacokinetic model for pyrimethamine (PYR) and sulfadoxine (SDX) in children with congenital toxoplasmosis. METHODS: Children were treated with PYR (1.25 mg kg(-1)) and SDX (25 mg kg(-1)) (Fansidar) plus folinic acid (Lederfoline) 5 mg). Plasma concentrations, available from a therapeutic drug monitoring database, were determined by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a nonlinear mixed effects model. RESULTS: Eighty-nine children, aged 1 week to 14 years and weighing 2.9-59 kg, were available for evaluation. Both PYR and SDX concentration-time profiles were best described by a one-compartment open model. Volume of plasma distribution (V) and clearance (CL) were significantly related to body weight (BW) using an allometric function. Typical CL and V estimates (95% confidence interval), for a child weighing 11 kg were 5.50 (5.28, 5.73) l day(-1) and 36 (33, 39) l for PYR and 0.26 (0.25, 0.27) l day(-1) and 2.1 (1.9, 2.3) l for SDX. For BW between 3.5 and 60 kg, plasma half-lives were predicted to vary from 4.0 to 5.2 days for PYR, and from 5.0 to 7.5 days for SDX. CONCLUSION: This study indicated that body weight influences PYR and SDX pharmacokinetics in children. To optimize PYR/SDX combination treatment in congenital toxoplasmosis, short dosing intervals in very young low-wight children are probably appropriate.     

Population pharmacokinetics of oral diclofenac for acute pain in children

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Diclofenac is an effective oral analgesic for acute postoperative pain. In adults 25 mg is half as effective as 50 mg, but 50 mg and 100 mg are similarly effective (ceiling effect). Diclofenac has linear pharmacokinetics in this range.
• Diclofenac is frequently used ‘off-label’ in children for acute pain but optimum dosing is unclear (dosing of diclofenac in clinical paediatric studies ranges from 0.5–2.5 mg kg⁻¹). There is currently no licensed oral paediatric formulation of diclofenac.

WHAT THIS STUDY ADDS

• Using a new diclofenac oral suspension, a dose of 1 mg kg⁻¹ in children aged 1 to 12 years gives a similar exposure to 50 mg in adults; paediatric patients are unlikely to benefit from higher doses.

AIMS

To develop a population pharmacokinetic model for a new diclofenac suspension (50 mg 5 ml⁻¹) in adult volunteers and paediatric patients, and recommend a dose for acute pain in children.

METHODS

Blood samples were drawn at the start and end of surgery, and on removal of the venous cannula from 70 children (aged 1 to 12 years, weight 9 to 37 kg) who received a preoperative oral 1 mg kg⁻¹ dose; these were pooled with rich (14 post-dose samples) data from 30 adult volunteers. Population pharmacokinetic modelling was undertaken with NONMEM. The optimum adult dose of diclofenac for acute pain is 50 mg. Simulation from the final model was performed to predict a paediatric dose to achieve a similar AUC to 50 mg in adults.

RESULTS

A total of 558 serum diclofenac concentrations from 100 subjects was used in the pooled analysis. A single disposition compartment model with first order elimination and dual absorption compartments was used. The estimates of CL/F and V_D/F were 53.98 l h⁻¹ 70 kg⁻¹ and 4.84 l 70 kg⁻¹ respectively. Allometric size models appeared to predict adequately changes in CL and V_D with age. Of the simulated doses investigated, 1 mg kg⁻¹ gave paediatric AUC_{(0, 12 h)} to adult 50 mg AUC_{(0, 12 h)} ratios of 1.00, 1.08 and 1.18 for ages 1–3, 4–6 and 7–12 years respectively.

CONCLUSIONS

This study has shown 1 mg kg⁻¹ diclofenac to produce similar exposure in children aged 1 to 12 years as 50 mg in adults, and is acceptable for clinical practice; patients are unlikely to obtain further benefit from higher doses.