Population pharmacokinetics of carbamazepine in Singapore epileptic patients

AIMS: To document the population pharmacokinetics of carbamazepine in patients with epilepsy living in Singapore, the majority of whom are of Chinese origin and others of minority races. METHODS: Steady-state plasma carbamazepine concentration data were gathered during routine care from various hospitals in Singapore for patients with epilepsy. Age, body weight, gender, race, formulation and concurrent medication (for other illnesses) were the fixed effects (covariates) tested simultaneously for their influence on the population mean of carbamazepine clearance, using the nonlinear mixed-effects model, in the NONMEM program. RESULTS: No age, gender, race, or formulation-related effect was found. Body weight (W), age (A) and concurrent medication with phenobarbitone (PB) emerged as the determinants of carbamazepine clearance (CL). The final regression model for carbamazepine clearance found best to describe the data was CL = 40.7 x A(0.494) x W(-1.17) x 1.44PB where CL is in l day(-1) kg(-1), A is in years, W is in kg and PB = 0 for a patient on carbamazepine only and PB = 1 for a patient on concomitant PB. The corresponding interindividual variability (CV%) in CL, described by using an exponential model, was 21.4%, and the residual error, described by using an exponential error model, was 18.2%. Predictive performance of this population covariate model was evaluated by Bayesian forecasting in a similar, but independent cohort of patients. There was no statistically significant bias between predicted and measured plasma carbamazepine concentrations. The population mean value of carbamazepine clearance obtained was similar to that previously reported for patients with a very different ethnic (Caucasians and Blacks) or geographical background (South Africa, Europe and USA). CONCLUSIONS: The derived covariate regression model reasonably predicted concentrations in the separate validation Singapore patient data set. The correlation between carbamazepine clearance and patient-specific characteristics may thus allow dosage adjustment to be made to achieve target steady-state plasma concentrations.     

Population pharmacokinetics of free carbamazepine in adult Omani epileptic patients

OBJECTIVE: The aim of this study was to define the pharmacokinetic profile of free carbamazepine (F-CBZ) in adult Omani epileptic patients in order to improve on dosing schedules through population pharmacokinetic analysis using the NONMEM program. METHOD: Steady-state trough F-CBZ serum concentrations, carbamazepine (CBZ) dosing history and associated information were collected prospectively. RESULTS: Forty-eight patients with two or more available F-CBZ serum concentrations (total of 149 dose/serum concentration pairs) met our inclusion criteria. Patients were taking CBZ (200-1200 mg/day) in monotherapy. The analysis assumed a one-compartmental open model with first-order absorption and elimination. The apparent clearance (CL/F) and apparent volume of distribution (V/F) and their interindividual variabilities were estimated using the program. The population estimates for clearance (CL; modelled independently of dose) and volume of distribution were 13.2 +/- 0.6 l/h and 525 +/- 44 1, respectively. However, CL increased as a function of dosing rate and consequently was modelled as a linear function of steady-state concentration. In order to validate these results, the predictions of the population model were tested against data from 13 further patients subjected to the same inclusion criteria but who were not included in the original analysis. The predictions were good, being unbiased (P=0.31), and had an average deviation from the observed values of 18%. CONCLUSION: In order to establish steady-state dosage regimens, a population pharmacokinetic model is proposed, based on the patient's dose, to estimate the individual CL for an Omani epileptic patient receiving CBZ in monotherapy.     

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 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.     

中国成年癫痫患者奥卡西平活性代谢产物的群体药动学

目的：建立中国癫痫患者奥卡西平活性代谢产物10-羟基卡马西平的群体药动学模型,进而取得对癫痫患者有效的数据参数,为癫痫患者给出有针对性的给药治疗依据。方法：通过实地收集参与研究使用奥卡西平片患者血液药物含量监测数据,利用NLME软件来实现近似群体药动学数学逻辑模型,建立基础模型和统计学模型后,考察年龄、体质量、合并用药等潜在影响10-羟基卡马西平药动学的相关变量参数,将Bootstrap估得的和原始数据估得的参数值进行对比分析,确保模型对实验有效以及测验结果稳定,对建立的模型通过自举法进行验证。结果：共收集了119个患者的180个浓度点,所建立的10-羟基卡马西平的群体药动学模型符合一级吸收、一级消除的一室模型,CL/F及V_d/F群体值分别为1.22 L·h^-1和43.21 L;K_a固定为0.5 h^-1。体表面积对10-羟基卡马西平的清除率有显著影响。结论：初步建立了中国癫痫患者奥卡西平活性代谢产物10-羟基卡马西平的群体药动学模型,为癫痫患者给出了有针对性的给药治疗依据。     

Population pharmacokinetics modeling of levetiracetam in Chinese children with epilepsy

Aim:

To establish a population pharmacokinetics (PPK) model of levetiracetam in Chinese children with epilepsy.

Methods:

A total of 418 samples from 361 epileptic children in Peking University First Hospital were analyzed. These patients were divided into two groups: the PPK model group (n=311) and the PPK validation group (n=50). Levetiracetam concentrations were determined by HPLC. The PPK model of levetiracetam was established using NONMEM, according to a one-compartment model with first-order absorption and elimination. To validate the model, 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 calculated.

Results:

A regression equation of the basic model of levetiracetam was obtained, with clearance (CL/F)=0.988 L/h, volume of distribution (V/F)=12.3 L, and K_a=1.95 h⁻¹. The final model was as follows: K_a=1.56 h⁻¹, V/F=12.1 (L), CL/F=1.04×(WEIG/25)^0.583 (L/h). For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95%CI were 9.834 (−0.587–197.720), 50.919 (0.012–1286.429), 1.680 (0.021–34.184), and 0.0621 (−1.100–1.980). For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were 0.199 (−0.369–0.563), 0.002082 (0.00001–0.01054), 0.0293 (0.001−0.110), and 0.153 (−0.030–1.950).

Conclusion:

A one-compartment model with first-order absorption adequately described the levetiracetam concentrations. Body weight was identified as a significant covariate for levetiracetam clearance in this study. This model will be valuable to facilitate individualized dosage regimens.     

中国患者异丙酚群体药代动力学(英文)

目的:用NONMEN程序分析中国患者群体药代动力学,并定量研究性别、年龄和体重对异丙酚药代参数的影响。方法:研究了76例择期手术的患者(男37例、女39例、年 龄19-77岁、体重39-86kg),共收集1459个血液标本。用NONMEN方法分析清除率和分布容积的个体间变异以及年龄、体重和性别的影响。结果:可用三室模型模拟异丙酚的药代动力学参数。体重可影响异丙酚的中央室、浅外周室和深外周室的清除率以及中央室的分布容积,而浅外周室和深外周室的分布容积保持不变。体重60kg的成人的上述药代参数的估计值分别为:1.56L/min、0.737L/min、0.360L/min、12.1L、43L、213L。老人随年龄的增大而清除率和中央室的分布容积减少。结论:中国人的异丙酚的药代动力学可用标准三室模型描述,年龄和体重可影响模型参数。因此根据患者的个体药代参数可改善靶控输注的精密度。     

左乙拉西坦在癫痫患儿中的群体药动学研究

目的建立癫痫患儿口服左乙拉西坦的群体药动学(PPK)模型,并用此模型探讨左乙拉西坦在儿童患者群体内的药动学特征。方法收集344例癫痫患儿口服左乙拉西坦后的血药浓度数据和临床资料。将患儿随机分为两组,模型组(n=259)采用NLME程序进行PPK分析,建立一房室药动学模型(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Ka、Vd和CL的影响。用拟合优度、自举法对最终模型的性能进行内部验证。采用最终模型预测验证组(n=85)患儿的血药浓度,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:Ka(h-1)=1.01×eηKa,Vd(L·kg-1)=[0.42+0.000 35×(AGE-56)]×eηVd,CL(L·kg-1·h-1)=[0.05-0.009 5×(ln WT-2.83)]×eηCl;年龄(AGE)正相关影响Vd,体重的自然对数值(ln WT)负相关影响CL。拟合优度、自举验证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=0.01 mg·L-1,MAE=0.91 mg·L-1,MSE=1.16(mg·L-1)2,RMSE=1.08 mg·L-1。血药浓度实测值和最终模型的个体预测值的决定系数R2=0.990 6。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癫痫患儿口服左乙拉西坦后的PPK模型,模型结构表明左乙拉西坦体重校正的清除率随患儿年龄和体重的增加有下降趋势。     

氯氮平在中国精神分裂症人群的群体药物动力学研究

本研究旨在考察口服氯氮平 (clozapine) 在中国精神分裂症患者中的群体药物动力学特征, 探讨各项动力学参数与人口统计学因素及CYP1A2酶基因多态性的关系, 通过建立群体药物动力学模型指导临床个体化给药。研究中采集了临床服用氯氮平的183例精神分裂症患者的626份稳态血样本资料, 随机分组为建模组 (168例) 和外部验证组 (15例)。用非线性混合效应模型 (NONMEM) 程序中的一级评估法 (first-order estimation, FO) 对建模组的数据进行分析, 估算清除率 (CL/F)、表观分布容积 (V/F) 和吸收速率常数 (K_a) 的群体值, 并且定量评价人口统计学指标和CYP1A2酶基因型因素对药物动力学参数的影响。建模中单室一级吸收和消除模型能够较好地拟合数据。最终模型包含了经体表面积归一化的单日剂量 (DBSA) 和吸烟 (SMOK) 因素对CL/F的影响。CL/F (非吸烟组)、V/F和K_a的群体典型值分别为28.5 L·h⁻¹ (5.05%)、1 290 L (16.7%) 和2.26 h⁻¹ (fixed), 相应的个体间变异分别为42.2%和10.0%。研究发现吸烟组的清除率有所上升。观测值与预测值之间的残留误差SD为45.8 μg·L⁻¹。     

他克莫司在中国肾移植患者中的群体药物动力学研究

本研究旨在考察口服他克莫司(tacrolimus)在中国肾移植患者中的群体药物动力学特征并探讨群体药物动力学参数和相关因素间的关系。研究中回顾性搜集了58例肾移植患者的802份他克莫司稳态全血样本资料。患者随机分为模型建立组(41例)和模型验证组(17例)。用非线性混合效应模型(NONMEM)程序中的一级评估法(first-order estimation，FO)对模型建立组的数据进行分析。计算清除率(CL/F)、表观分布容积(V/F)的群体典型值，定量评价人口统计学指标、生化指标和合并用药等固定效应因素对药物动力学参数的影响。单室一级吸收和消除模型能够较好地拟合数据。最终模型包含了移植术后时间(POD)、红细胞压积(HCT)、谷草转氨酶(AST)、合并使用佩尔地平(NICA)和地尔硫(DIL)等对CL/F的影响。用模型验证组数据进行验证的结果表明观测值和模型预测值之间没有明显的偏倚，模型的稳定性和准确度较好。CL/F和V/F的群体典型值分别为21.7 L·h^-1和241 L；相应的个体间变异分别为41.6%和49.7%。观测值与预测值之间的残差SD为2.19 μg·L^-1。本文建立的模型可以为临床他克莫司剂量选择提供一定参考。     

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 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.     

Influence of UDP-glucuronosyltransferase polymorphisms on valproic acid pharmacokinetics in Chinese epilepsy patients

Purpose

The aim of this study was to investigate the genetic polymorphisms of UGT1A3, UGT1A6, and UGT2B7 in Chinese epilepsy patients and their potential influence on the pharmacokinetics of valproic acid (VPA).

Methods

The genetic architectures of UGT1A3, UGT1A6, and UGT2B7 in 242 epilepsy patients were detected by DNA sequencing and PCR-restriction fragment length polymorphism. Steady-state plasma concentrations of VPA in 225 patients who had received VPA (approx. 250–1,000?mg/day) for at least 2 weeks were determined and associated with UGT polymorphisms.

Results

The allelic distribution of UGT1A3 in our Chinese epilepsy patients was significantly different from that in healthy subjects based on reference data. The standardized trough plasma concentration (C_S) of VPA was much lower in our patients with the UGT1A3*5 variant than in the wild type carriers (3.24?±?1.05 vs. 4.68?±?1.24?μg·kg·mL^-1·mg^-1, P?Conclusion Our results suggest that UGT1A3*5 may be an important determinant of individual variability in the pharmacokinetics of VPA and that it may be necessary to increase VPA dose for UGT1A3*5 carriers to ensure its therapeutic range of 50–100?μg/mL.     

Population pharmacokinetics of lamotrigine adjunctive therapy in adults with epilepsy

Plasma concentrations of lamotrigine, an antiepileptic drug obtained in three adult controlled clinical trials conducted in the United States were pooled and analyzed using NONMEM, a population pharmacokinetic computer program, to facilitate development of dosing guidelines. A total of 2,407 lamotrigine plasma concentrations from 527 patients with epilepsy were analyzed. Regression equations for oral clearance were developed as a function of body size, age (18-64 years), gender, race, and use of concomitant antiepileptic drugs. The population mean apparent oral clearance of lamotrigine in adult patients receiving one concomitant enzyme-inducing antiepileptic drug and not valproic acid was estimated to be 1 mL/min/kg. Gender and age did not affect clearance significantly. On average, clearance was reduced by 25% in non-whites and increased by 13% in patients receiving more than one concomitant enzyme-inducing antiepileptic agent. Lamotrigine did not influence the disposition of phenytoin or carbamazepine. Dosing adjustments for lamotrigine in patients receiving concomitant enzyme-inducing antiepileptic drugs and not valproic acid should not be necessary for age, gender, or the number of concomitant enzyme-inducing antiepileptic drugs. Lamotrigine does not influence the dosing requirements for phenytoin or carbamazepine.     

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).     

Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patients

AIMS

This study was aimed at determining the population pharmacokinetics of sirolimus and identifying factors that explain pharmacokinetic variability in de novo Chinese adult renal transplant patients.

METHODS

Data were retrospectively extracted from a formal multicentre clinical trial, which was originally designed to evaluate the safety and efficacy of ciclosporin dose reduction and ciclosporin elimination in patients receiving sirolimus. All patients received 12-month treatment, i.e. induction therapy with ciclosporin, sirolimus and corticosteroids during the first 3 months followed by either ciclosporin dose reduction or ciclosporin discontinuation thereafter. Eight-hundred and four sirolimus trough blood concentrations (C₀) from 112 patients were used to develop a population pharmacokinetic model using the nonmem program. A one-compartment model with first-order absorption and elimination was selected as the base model. The influence of demographic characteristics, biochemical and haematological indices, ciclosporin daily dose, ciclosporin C₀ as well as other commonly used co-medications were explored.

RESULTS

The typical values with interindividual variability for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 10.1 l h⁻¹ (23.8%) and 3670 l (56.7%), respectively. The residual variability was 29.9%. CL/F decreased significantly with silymarin or glycyrrhizin co-therapy in hepatically impaired patients, and with increasing total cholesterol levels or ciclosporin C₀. Moreover, CL/F increased nonlinearly with increasing sirolimus daily dose. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5% of the estimates from nonmem.

CONCLUSIONS

These results provide important information for clinicians to optimize sirolimus regimens in Chinese renal transplant patients.     

The pharmacokinetics of carbamazepine

Summary The time-courses of plasma carbamazepine concentrations were followed in six apparently healthy adult subjects who, at different times, took single oral drug doses of 200, 400, 500, 600, 700, 800 and 900 mg. There were some suggestions of impaired bioavailability of the drug when given in tablet form. The following values were obtained for various pharmacokinetic parameters:k _abs =0.176±0.209 h^–1;k=0.0203±0.0055 h^–1; T_1/2=37.5±13.1 h; V_D=0.825±0.1041 · kg^–1; Clearance=0.0163±0.0061 l · kg^–1. The elimination rate constant showed a statistically significant increase with increasing drug dose. This may help explain the clinical observation that the rate of rise of steady state plasma carbamazepine concentrations tends to decrease with dose increase in patients taking carbamazepine alone.