基于meta分析的利培酮群体药代动力学研究及其在中国精神分裂症患者临床治疗药物监测中的预测应用

本文应用基于meta分析的群体药动学研究方法分析利培酮及其代谢产物的群体药物动力学特征。文中首先筛选发表于1995至2011年的文献,得到18篇符合录入排除标准的文献,并在文献数据的基础上建立了利培酮及其活性代谢产物9-羟基利培酮的群体药动学模型。建立的模型用二室模型描述原药利培酮体内过程,一室模型描述活性代谢产物9-羟基利培酮的体内过程,并在药物的吸收过程中加入了原药的首过代谢过程。模型得到原药和代谢产物的系统清除率分别为7.66 L/h和7.38 L/h,表观分布体积分别为70.6 L和117 L。建立的模型通过1000次仿真的可视化检验评价模型的拟合程度。本文还利用42例精神分裂症患者临床治疗药物监测数据来评价模型对于中国患者人群中利培酮血药浓度的预测性。本研究证明通过文献数据所建的模型是可靠的,可以用作目标群体个体化治疗的依据。     

64例老年患者万古霉素血药浓度监测结果分析

目的:通过分析64例老年肺部感染患者万古霉素血药浓度的监测结果,为临床合理用药提供参考.方法:采用荧光偏振免疫法测定万古霉素的血药浓度,对64例157例次血药浓度监测结果进行比较分析.结果:患者万古霉素血清峰浓度和谷浓度均在治疗窗范围内的仅占40% 左右,而谷浓度高于正常范围及峰浓度低于正常范围的约占50% ;首剂饱和方案组与首剂未饱和方案组中血清峰浓度比较有显著性差异,而谷浓度无显著性差异;肾功能正常组患者用药前、后内生肌酐清除率有显著性差异,尿素氮无显著性差异,而肾功能损害组患者用药前、后尿素氮及内生肌酐清除率均无显著性差异;近45% 的患者给药方案为500 mg,每日2~3 次,约75% 的患者未能达到有效峰浓度,约60% 的患者谷浓度超过正常水平.结论:老年感染患者使用万古霉素个体差异很大且多数患者伴有肾功能轻中度损害,应尽量给予首剂饱和方案并对其进行血药浓度监测,以利于实现个体化给药,进而提高该药应用的有效性和安全性.     

Population pharmacokinetics of doxorubicin in Indian cancer patients using NONMEM

The population pharmacokinetics of doxorubicin were evaluated based on a mixed-effect model using the NONMEM (VI) program. Doxorubicin in plasma was measured using high-performance liquid chromatography. Plasma concentration measurements (85 plasma samples) of doxorubicin from 28 patients with cancer receiving doxorubicin (with other co-medication) ranging from 20–120?mg by infusion over 1–2?h were analyzed according to a two-compartment model both in FO and FOCE methods. Additive proportional error model was used to describe inter-individual and residual variability. The influence of covariates such as age, body surface area, gender, and clinical laboratory values (SGOT, SGPT) on total body clearance (CL) and volume of distribution (Vd) were examined. No covariate was found to affect the CL and Vd of unchanged doxorubicin. The CL and Vd estimated by FO method were 1.42?L/h and 51.1?L, respectively, and FOCE method are 1.43?L/h and 51.4?L, respectively. The inter-individual variability for CL and Vd and residual variability were 45.8%, 36%, and 12.6%, respectively. The population means and inter-individual and residual variability of pharmacokinetics of doxorubicin were evaluated using the NONMEM program. The results of this study show that the population pharmacokinetic approach could be useful to manage doxorubicin cardio toxicity using sparse data in a clinical setting.     

Population pharmacokinetics of arbekacin in burn patients

The aim of this study was to estimate the pharmacokinetics (PK) of arbekacin in burn patients using a population–PK approach. Therapeutic drug monitoring data consisting of 126 plasma concentrations (including 17 values that were below the quantitation limit) from 47 burn patients were retrospectively analyzed using a mixed effect method (NONMEM, ver. 6.0). Covariates, such as burn index, age, sex, among others, were tested on the basic one-compartment model. In the basic model, positive correlations of body weight (WT) and creatinine clearance (CLcr) on total clearance (CL) and volume of distributions (V) were assumed. In the final model, V increased with burn index (BI). The final model was: ;. Between-subject variability in terms of CL and V were 35 and 39%, respectively. The CL of our burn patients was significantly greater than that reported in unburned patients, and V increased proportionally with increasing BI.     

群体药物动力学及其在儿科中的临床应用

群体药物动力学(PPK)是一门新兴学科。儿科PPK研究主要聚焦于儿童治疗药物监测和个体化给药等。本文综述PPK研究的基本概念、前提条件、方法及其在儿科中的临床应用进展。     

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。     

ICU老年患者液体出入量对万古霉素药代动力学的影响

目的 研究液体出入量对ICU老年患者万古霉素药代动力学的影响.方法 完全随机选择8例ICU中应用万古霉素的老年患者,记录其每日液体出入量,并采集患者血液,利用高效液相色谱法测定万古霉素的血药浓度,计算药代动力学参数,对万古霉素药代动力学参数与患者每日出入量之间的关系给予统计学分析.结果 ICU老年患者年龄(71 ±11)岁,急性生理学与慢性健康状况评分系统Ⅱ(APACHEⅡ)评分(17.13±3.13)分,液体净出入量(375±123)ml,分布半衰期(t1/2α)(0.45±0.27)h,清除半衰期(t1/2β)(6.86±3.42)h,浓度时间曲线下面积(AUC)(137.9±19.9) mg/(h·L),峰值浓度(Cmax)(36.14±10.30) mg/L,清除率(61.56±29.11) ml/min,表观分布容积(0.28±0.14)L/kg.ICU老年患者与正常老年人相比,表观分布容积差别有统计学意义(P＜0.01).ICU老年患者APACHEⅡ评分与液体净出入量和万古霉素t1/2β均呈正相关(r=0.811,P=0.015;r =0.035,P=0.035);液体出入量与血AUC呈负相关,与血t1/2β呈负相关(r=- 0.786,P=0.021).结论 当ICU患者的出入量平衡增加时,其万古霉素的杀菌效果可能会降低,难以达到预期疗效.     

群体药代动力学及其在新药研究中的应用

近年来新药临床研究越来越重视群体药代动力学的应用。群体药代动力学可以定量地描述病理、生理、合并用药等多种因素对药物代谢的影响，可将PK参数中的各种变异区分开，指导用药方案的调整，从而增强对新药有效性和安全性的评价。本文对群体药代动力学的研究方法及其在新药研究中的应用进行综述．     

Population pharmacokinetics of arginine glutamate in healthy Chinese volunteers

1.?The present study developed population pharmacokinetic models of arginine and glutamate in healthy Chinese volunteers. Two nonlinear mixed-effect models were developed using NONMEM® software (ICON Development Solutions, Ellicott City, MD) to describe the pharmacokinetic properties and to assess the relevant parameters as well as the inter-individual variability. The potential covariates were screened using stepwise approach and the stability and predictive capability of the models were performed using bootstrap and visual predictive check.

2.?The concentration time curves of arginine and glutamate were best described by a first-order elimination two-compartment model and a nonlinear elimination one-compartment model, respectively. The final parameter estimation of arginine for CL was 44.1?L/h. Q, V₁ and V₂ were 23?L/h, 20.3?L and 46?L, respectively. The final parameter estimation of glutamate for V_max and K_m were 18.8?mg/h and 77.2?mg/L, respectively. V for low dose and high dose was 23.1?L and 36.3?L, respectively.

3.?For arginine, weight was significant covariate on the apparent distribution volume of peripheral compartment. The gain in weight remarkably increases V_2. For glutamate, dose as a significant covariate on the apparent distribution volume was included, subjects received high dose (20?g) have remarkably higher V compared to subjects received low dose (10?g).     

老年心衰患者口服地高辛群体药动学模型的建立

目的:应用非线性混合效应模型计算国人老年心衰患者口服地高辛(digxion)群体药动学参数,以促进个体化给药。方法:采用荧光偏振免疫法(FPIA)测定84例老年患者120例次地高辛的血清浓度并收集相关临床指标,运用NONMEM软件建立群体药动学模型。结果:地高辛的药动学符合一室线性开放模型,固定效应参数中,体质量、剂量、血肌酐及尿素氮对参数有影响。最终回归模型中地高辛血药浓度估算值与实测浓度间线性关系良好。结论:用群体药动学模型分析常规监测数据可为老年患者个体化给药提供依据。     

Population pharmacokinetics of Cyclosporine and its clinical application

A population pharmaeokinetic model of eyelosporine （CsA） for clinical renal transplant patients was constructed to adjust CsA＇ s administration individually. A total of 2, 548 retrospective drug monitoring data were collected from 120 Chinese renal transplant patients receiving CsA. Population modeling was performed with NONMEM by a one-compartment model with first-order absorption and elimination. Six significant eovariates were included in the final model. It is postoperative days （POD）, total bilirubin level （TBIL）, current body weight （CBW）, age, concurrent metabolic inhibitors of CsA （INHI）, and hematocrit （HCT）. The population means for CL/F （28.5 L/h）, V/F （volume of distribution, 133 L）, and inter-patient vari-Fability （CV% = 19.7%） for CL/F were estimated. The model was further validated internally and externally, and was demonstrated to be effeetive and robust. Moreover, in order to put the result of population pharmaeokinetie studies into elinical praetiee, a database with the name of C- TDM for post renal transplantation patients based on the population model was established. Up on the availability of the information from elinic, the precision of the plasma concentration predieted with C-TDM was elassified into 3 levels,[第一段]     

Population pharmacokinetics of tolcapone in parkinsonian patients in dose finding studies

AIMS: To use pharmacostatistical models to characterize tolcapone's pharmacokinetics in parkinsonian patients, and to identify any demographic subpopulations which may be at risk of either under- or over-exposure to this catechol-O-methyltransferase (COMT) inhibitor. METHODS: Four hundred and twelve patients participated in three multicentre, parallel, double-blind, placebo-controlled, dose-finding studies and received either placebo or tolcapone (50, 200 or 400 mg three times daily) in addition to levodopa/decarboxylase inhibitor therapy. Sparse blood samples were obtained from 275 patients for tolcapone assay and the concentrations (1414 in total) were analysed using the NONMEM program. RESULTS: The pharmacokinetic model which best described the data was a two-compartment open model with first-order absorption and possibly a lag-time. Tolcapone pharmacokinetics were shown to be stable, with no systematic trend between 2 and 6 weeks of treatment. The absorption of the drug was shown to be rapid and concomitant food intake had only a minor effect on the relative bioavailability (10-20% reduction compared with fasting). The overall clearance of tolcapone could be estimated with good precision (approximately 4. 5-5 l h-1 ), and none of the investigated covariates (e.g. sex, age, body weight) had any clinically significant influence on this parameter. The volume of distribution showed relatively high variability and was calculated to be approximately 30 l, leading to an estimated half-life in patients of approximately 5-8 h. CONCLUSIONS: Using sparse concentrations and mixed effect-effects modelling analysis it is possible to describe the pharmacokinetics of tolcapone in parkinsonian populations. The parameter estimates obtained agreed with those obtained from conventional pharmacokinetic studies and no subpopulation was shown to be at risk of either under- or over-exposure to tolcapone.     

Population pharmacokinetics of domperidone in preterm neonates

Purpose  A population pharmacokinetic analysis was performed to define domperidone pharmacokinetic parameters in preterm neonates, as no pharmacokinetic data are available in this population. Methods  An oral domperidone solution was administered (0.75 mg/kg per day) in 32 preterm neonates (64 samples). Domperidone plasma concentration was measured by high-performance liquid chromatography (HPLC) assay, and a one-compartment model with first-order absorption was fitted to the data using NONMEM version V level 1.1. Results  The mean peak and trough plasma concentration values of domperidone were, respectively, 25.3 ± 20.5 ng/ml and 15.4 ± 11.4 ng/ml (mean ± standard deviation). The pharmacokinetic parameters (interindividual variability%) were clearance (Cl/F) = 0.92 L/h (51.6%), volume of distribution (Vd/F) = 0.405 L (68%), and absorption constant rate (Ka) = 0.0843 h⁻¹ (55.8%). The clearance is not lower than values reported in adults. No influence of covariates (postnatal age, prematurity, weight, gender) on domperidone pharmacokinetic parameters was found. Conclusion  This pilot study designed with a limited sampling strategy showed that domperidone plasma concentrations were consistent with those reported in adults, suggesting that domperidone dosage regimen currently used in preterm neonates is suitable.     

拉氧头孢对映异构体在儿童群体中的药动学研究和剂量优化

目的:建立拉氧头孢对映异构体在儿童患者中的群体药动学模型,研究拉氧头孢在儿童患者体内的药动学特点,为拉氧头孢在儿童患者中的个体化用药提供依据。方法:检测145例静脉滴注拉氧头孢患儿的血药浓度,收集患儿临床资料。采用非线性混合效应模型法建立拉氧头孢对映异构体在儿童患者群体中药动学模型,并用自举法、拟合优度图和正态化预测分布误差进行验证。采用蒙特卡洛模拟评价不同给药方案的合理性。结果:四房室模型可以较好描述拉氧头孢对映异构体在儿童患者体内的药动学特征。最终模型稳定,预测结果可靠。拉氧头孢R和S对映异构体的表观分布容积(V_d)分别为5.57 L和4.15 L,清除率(CL)分别为0.78 L·h^-1和1.32 L·h^-1。体质量对拉氧头孢异构体药动学参数有显著影响。结论:该研究成功建立了拉氧头孢对映异构体在儿童患者群体中的药动学模型,可为拉氧头孢的个体化用药提供参考。     

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。     

万古霉素在血液透析患者中的药物动力学研究

本文对５例尿毒症血透患者，静脉滴注万古霉素１ｇ后，６ｈ内血中药物浓度变化，进行其药动学研究。采用荧光偏振免疫法（ＦＰＩＡ），测定血清中万古霉素浓度，以３Ｐ８７程序，按静脉滴注二房室模型计算其药动学参数。结果显示万古霉素在肾功能衰竭患者中具有难经透析和消除的动力学特点。一次给药可维持相当长的有效血药浓度。     

Population pharmacokinetics of duloxetine in Japanese pediatric patients with major depressive disorder

The objectives of this analysis were to characterize the pharmacokinetics of duloxetine in Japanese pediatric patients aged 9–17 years with major depressive disorder (MDD) and to explore potential intrinsic factors affecting its pharmacokinetics. A population pharmacokinetic (PK) model was developed with plasma steady-state duloxetine concentrations from Japanese pediatric patients with MDD in an open-label long-term extension trial in Japan (ClinicalTrials.gov Identifier: NCT03395353). Duloxetine pharmacokinetics in Japanese pediatric patients was well described by a one-compartment model with first-order absorption. The population mean estimates of CL/F and V/F of duloxetine were 81.4 L/h and 1170 L, respectively. Patient intrinsic factors were assessed for their potential influence on duloxetine apparent clearance (CL/F). Only sex was identified as a statistically significant covariate of duloxetine CL/F. Duloxetine pharmacokinetic parameters and model-predicted duloxetine concentrations at steady state in the Japanese pediatric population were compared with those in Japanese adults. The mean duloxetine CL/F in pediatrics is slightly higher than adults, it is, however, expected that comparable steady-state duloxetine exposure in pediatric patients can be achieved with the approved dose regimen for adults. The population PK model provides useful information to understand the pharmacokinetic characteristics of duloxetine for Japanese pediatric patients with MDD.ClinicalTrials.gov identifierNCT03395353     

Population pharmacokinetics of tacrolimus in full liver transplant patients: modelling of the post-operative clearance

Objective To investigate the population pharmacokinetics of tacrolimus in an adult liver transplant cohort using routine drug monitoring data and to identify patient characteristics that influence pharmacokinetic parameters.Methods Tacrolimus pharmacokinetics was studied in 37 adult patients using a population approach performed with NONMEM.Results A one-compartment open model with linear absorption and elimination adequately described the data. The apparent clearance (CL) was approximately zero in the immediate post-operative days (PODs) and then rapidly increased as a function of POD to reach a plateau. This was modelled as a sigmoid relationship with the characteristic parameters CL_max (plateau), TCL₅₀ (time to obtain 50% of the plateau) and gamma (coefficient of sigmoidicity). This clearance model was thought to describe the hepatic function regeneration after transplantation. Typical population estimates (percentage inter-individual variability) of CL_max, TCL₅₀, and gamma and apparent distribution volumes (V) were 36 l/h (43%), 6.3 days (33%), and 4.9 l and 1870 l (49%), respectively. The CL_max was negatively related to plasma albumin, and TCL₅₀ was positively related to aspartate amino transferase (ASAT). Bayesian estimations performed at different POD times indicated that acceptable precisions in individual pharmacokinetic predictions could be obtained after the 15th POD.Conclusion Tacrolimus clearance modelling showed that there was a large variation in individual CL estimates up to the 15th day post-surgery. After this period, the mean error resulting from the Bayesian estimation was strongly decreased and this estimation method could be applicable and should limit tacrolimus monitoring.     

Population pharmacokinetics and pharmacodynamics of warfarin in healthy young adults

The population pharmacokinetics and pharmacological response — prothrombin complex activity and factor VII activity — were studied in a group of 48 normal, healthy young volunteers. Population parameter estimates were obtained using a standard two-stage method, a nonlinear mixed effect model (NONMEM) and a two-stage Bayesian method (EM algorithm). A modified sigmoid-Imax model was used to relate the concentration of s-warfarin to the rate of clotting factor synthesis. The three methods produced similar estimates of the population pharmacokinetic parameters, although the standard two-stage method overestimated the contribution of the pharmacokinetic parameters to the interindividual variability. It was not possible to partition the interindividual variability in response between the pharmacodynamic parameters with the NONMEM procedure: the estimates obtained from the EM algorithm were generally in good agreement with those obtained using the standard two-stage approach. The variability in the warfarin concentration contributed at most only 40% of the observed variability in the pharmacological response, and then only for times greater than 96 h after the dose. Most of the variability in the pharmacodynamics was due to interindividual differences in the clotting factor degradation rate constant and C_50,s, the s-warfarin concentration causing a 50% decrease in synthesis rate.