有限采样法对麦考酚酸进行血药浓度监测

目的:制订肾移植病人中麦考酚酸(MPA)的血药浓度监测的有限采样法方案。方法:采用高效液相色谱法测定13例肾移植病人服用麦考酚酸酯后不同时间点的总的和游离的MPA血药浓度。线性梯形法计算0～12 h药时曲线下面积(AUC0-12),逐步回归法建立多元回归模型,并与文献报道进行比较。结果:服药后1,2,4 h的MPA血药浓度(c1,c2,c4)预测总的和游离MPA浓度AUC0-12最佳。总的和游离浓度的回归模型分别为2．135+1．186·c1+1．217·c2+4．191·c4和0．194+1．149·c1+0．819·c2+2．759·c4。结论:c1,c2,c4估算 AUC0-12的有限采样法可用于麦考酚酸的临床血药浓度监测。     

有限采样法估算口服吡格列酮制剂的生物等效性

目的建立有限采样法模型估算盐酸吡格列酮(PGT)制剂的生物等效性。方法以健康志愿者口服PGT参比制剂后的血药浓度数据建模，有限采样法建立多元回归模型估算C_max和AUC_0-t。模型的内部和外部验证分别以Jackknife法和Monte Carlo法生成的模拟数据进行。选择最佳模型进行生物等效性评价。结果给药后1.5 h和2.5 h血药浓度(C_1.5和C_2.5)估算C_max的准确性较好，C_1.5和C₉估算AUC_0-t的准确性较好，平均预测误差<5%、平均绝对误差<9%，参数预测误差超过±20％的样本数<5%。生物等效性评价结果与经典法一致。结论有限采样法估算口服PGT制剂的生物等效性是可行的，为生物等效性研究提供新的思路和方法。     

Optimal sampling times for pharmacokinetic experiments

A sequential estimation procedure is presented which uses optimal sampling times to estimate the parameters of a model from data obtained from a group of subjects. This optimal sampling sequential estimation procedure utilizes parameter estimates from previous subjects in the group to determine the optimal sampling times for the next subject. Parameter estimates obtained from the optimal sampling procedure are compared to those obtained from a conventional sampling scheme by using Monte Carlo simulations which include noise terms for both assay error and intersubject variability. The results of these numerical experiments, for the two examples considered here, show that the parameter estimates obtained from data collected at optimal sampling times have significantly less variability than those generated using the conventional sampling procedure. We conclude that optimal sampling and preexperiment simulation may be useful tools for designing informative pharmacokinetic experiments.Presented at the First Annual Conference of the American College of Clinical Pharmacy, Boston, July 1980.     

有限采样策略估算心脏移植受者霉酚酸体内暴露的研究

目的 用有限采样策略(LSS)建立心脏移植受者霉酚酸(MPA)血药浓度-时间曲线下面积(AUC)的简化预测模型.方法 共收集20例心脏移植受者,术后按相同剂量连续服用吗替麦考酚酯片或其分散片至少7d后,采集不同时间的全血样本,用LC-MS/MS法测定血浆MPA浓度.用WinNonlin软件以非房室模型计算其药代动力学参...     

Clinical pharmacology of etoposide in children undergoing autologous stem cell transplantation for various solid tumours

1.?The population pharmacokinetics of high-dose etoposide was studied in a group of young children and adolescents.

2.?Twenty-six children and adolescent were administered high-dose etoposide as a continuous infusion over 24?h. Etoposide plasma concentration-time data was modelled using NONMEM^® 7. The effect of age, weight, serum creatinine (SCr), and gender on pharmacokinetic parameters (CL and V_d) were determined by a nonlinear mixed effect model.

3.?The pharmacokinetics of etoposide based on BSA dosing was best described with a 1-compartment structural model which was parameterised in terms of clearance (CL) and volume of distribution (V_d). An exponential error model was used to explain intersubject variability and a proportional error model was used to describe residual or intrapatient variability. The final model parameter estimates for the typical (normalised to 70?kg) values of CL and V_d were 2.31?L/hr and 17.5?L, respectively. The CL and V_d allometrically increased with weight with the power of 3/4 and 1, respectively. After accounting for weight dependence using the allometric scaling, age, serum creatinine, and gender did not have any influence on model parameters.

4.?The results of this children and adolescent population pharmacokinetic study indicates that etoposide pharmacokinetics were influenced by body weight on an allometric basis. The pharmacokinetic parameters CL and V_d increased with increasing weight similar to BSA.     

Population pharmacokinetics of mycophenolic acid and dose optimization with limited sampling strategy in liver transplant children

AIMS

The aims were to estimate the mycophenolic acid (MPA) population pharmacokinetic parameters in paediatric liver transplant recipients, to identify the factors affecting MPA pharmacokinetics and to develop a limited sampling strategy to estimate individual MPA AUC(0,12 h).

METHODS

Twenty-eight children, 1.1 to 18.0 years old, received oral mycophenolate mofetil (MMF) therapy combined with either tacrolimus (n= 23) or ciclosporin (n= 5). The population parameters were estimated from a model-building set of 16 intensive pharmacokinetic datasets obtained from 16 children. The data were analyzed by nonlinear mixed effect modelling, using a one compartment model with first order absorption and first order elimination and random effects on the absorption rate (k_a), the apparent volume of distribution (V/F) and apparent clearance (CL/F).

RESULTS

Two covariates, time since transplantation (≤ and >6 months) and age affected MPA pharmacokinetics. k_a, estimated at 1.7 h⁻¹ at age 8.7 years, exhibited large interindividual variability (308%). V/F, estimated at 64.7 l, increased about 2.3 times in children during the immediate post transplantation period. This increase was due to the increase in the unbound MPA fraction caused by the low albumin concentration. CL/F was estimated at 12.7 l h⁻¹. To estimate individual AUC(0,12 h), the pharmacokinetic parameters obtained with the final model, including covariates, were coded in Adapt II® software, using the Bayesian approach. The AUC(0,12 h) estimated from concentrations measured 0, 1 and 4 h after administration of MMF did not differ from reference values.

CONCLUSIONS

This study allowed the estimation of the population pharmacokinetic MPA parameters. A simple sampling procedure is suggested to help to optimize pediatric patient care.     

预测在儿童白血病患者治疗中依托泊苷的血药浓度

目的采用一个简单的、实用的方法评价临床个体患儿体内CYP3A酶活性;预测儿童白血病患者体内依托泊苷血药浓度、药动学参数。方法采用HPLC测定药物浓度,一点法计算药物消除半衰期,尿样法测定体内CYP3A酶活性。结果儿童白血病患儿体内依托泊苷药物浓度与CYP3A酶活性相关性较差,而其t1/2与个体在化疗前CYP3A酶活性变化的相关性较好。结论依托泊苷t1/2与儿童白血病患儿体内CYP3A酶活性有一定的相关性。     

Population pharmacokinetic analysis of clopidogrel in healthy Jordanian subjects with emphasis optimal sampling strategy

Aim: Clopidogrel is metabolized primarily into an inactive carboxyl metabolite (clopidogrel‐IM) or to a lesser extent an active thiol metabolite. A population pharmacokinetic (PK) model was developed using NONMEM® to describe the time course of clopidogrel‐IM in plasma and to design a sparse‐sampling strategy to predict clopidogrel‐IM exposures for use in characterizing anti‐platelet activity.Methods: Serial blood samples from 76 healthy Jordanian subjects administered a single 75 mg oral dose of clopidogrel were collected and assayed for clopidogrel‐IM using reverse phase high performance liquid chromatography. A two‐compartment (2‐CMT) PK model with first‐order absorption and elimination plus an absorption lag‐time was evaluated, as well as a variation of this model designed to mimic enterohepatic recycling (EHC). Optimal PK sampling strategies (OSS) were determined using WinPOPT based upon collection of 3–12 post‐dose samples.Results: A two‐compartment model with EHC provided the best fit and reduced bias in C_max (median prediction error (PE%) of 9.58% versus 12.2%) relative to the basic two‐compartment model, AUC_0‐24 was similar for both models (median PE% = 1.39%). The OSS for fitting the two‐compartment model with EHC required the collection of seven samples (0.25, 1, 2, 4, 5, 6 and 12 h). Reasonably unbiased and precise exposures were obtained when re‐fitting this model to a reduced dataset considering only these sampling times.Conclusions: A two‐compartment model considering EHC best characterized the time course of clopidogrel‐IM in plasma. Use of the suggested OSS will allow for the collection of fewer PK samples when assessing clopidogrel‐IM exposures. Copyright © 2013 John Wiley & Sons, Ltd.     

Development and validation of limited sampling strategies for prediction of the systemic exposure to the novel anticancer agent E7070 (N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide)

AIMS: E7070 is a novel, sulphonamide anticancer agent currently under clinical development for the treatment of solid tumours. The aim of this study was to develop and validate limited sampling strategies for the prediction of E7070 exposure in two different treatment schedules for phase II studies using the Bayesian estimation approach. METHODS: Data from two phase I dose finding studies were used in which E7070 was administered either as a single 1 h infusion or as a daily 1 h infusion for 5 days. Plasma concentration-time data from 75 patients were randomly divided into an index data set, used for the development of the strategies, and a validation data set. Population pharmacokinetic parameters were derived on the basis of the index data set. The D-optimality algorithm was used for the selection of optimal time points for both treatment schedules. The developed strategies were compared by assessment of their predictive performance of exposure, expressed as AUC (area under the plasma concentration vs time curve), in the validation data set. RESULTS: The developed population pharmacokinetic model comprised three compartments, with saturable distribution to one peripheral compartment and both linear and saturable elimination from the central compartment. For the 1 h infusion, a four sample strategy was selected which resulted in unbiased and accurate predictions of AUC (bias 0.74%, precision 13%). A five sample strategy was generated for the daily times five schedule yielding unbiased (bias 3.2%) and precise (12% precision) predictions of AUC. CONCLUSIONS: Optimal sampling strategies were developed and validated for estimation of E7070 exposure in two different treatment schedules. Both schedules enabled accurate and unbiased predictions of AUC.     

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

AIM

To develop a population pharmacokinetic model of ciclosporin (CsA) in haematopoietic allogeneic stem cell transplantation to facilitate a limited sampling strategy to determine systemic exposure (area under the curve [AUC]), in order to optimize CsA therapy in this patient population.

METHODS

The pharmacokinetics of CsA were investigated prospectively in 20 patients following allogeneic haematopoietic stem cell transplantation (HSCT). CsA was given twice daily, as a 3 h i.v. infusion starting at day 1 of the conditioning scheme, and orally later on, when oral intake was well tolerated. Fluconazole was given as antimycotic prophylaxis. Pharmacokinetic parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. A first order absorption model with lag time was compared with Erlang frequency distribution and Weibull distribution models. The influence of demographic variables on the individual empirical Bayesian estimates of clearance and distribution volume was tested. Subsequently two limited sampling strategies (LSS) were evaluated: posterior Bayesian fitting and limited sampling equations.

RESULTS

Twenty patients were included and 435 samples were collected after i.v. and oral administration of CsA. A two compartment model with first order absorption best described the data. Clearance (CL) was 21.9 l h⁻¹ (relative standard deviation [RSD]± 5.2%) with an inter-individual variability of 21%. The central volume of distribution (V_c) was 18.3 l (RSD ± 8.7%) with an inter-individual variability of 29%. Bioavailability (F) was 0.71 (RSD ± 9.9%) with and inter-individual variability of 25% and lag time (t_lag) was 0.44 h (RSD 5.5%). Weight, body surface area, haematocrit, albumin, ALAT and ASAT had no significant influence on pharmacokinetic parameters. The best multiple point combination for posterior Bayesian fitting, in terms of estimating systemic CsA exposure, appeared to be C0 + C2 + C3.Two selected LSS two time point equations and all selected three and four time point equations predicted de all AUC(0,12 h) within 15% bias and prediction.

CONCLUSIONS

The i.v. and oralcurves were best described with a two compartment model with first-order absorption with lag time. With the Bayesian estimators from this model, the area under the concentration−time curve in HSCT patients taking fluconazole can be estimated with only three blood samples (0, 2, 3 h) with a bias of 1% and precision of 4%.     

Population pharmacokinetics model and limited sampling strategy for intravenous vinorelbine derived from phase I clinical trials

AIMS: a) To characterize the pharmacokinetics of intravenous vinorelbine, b) to use a population analysis for the identification of patient covariates that might appreciably influence its disposition and c) to define a limited sampling strategy for further Bayesian estimation of individual pharmacokinetic parameters. METHODS: All data were collected from 64 patients (99 courses) entered in three different phase I trials that have been previously reported. All patients received vinorelbine as a 20 min infusion with dose levels ranging from 20-45 mg m-2. The population pharmacokinetic model was built in a sequential manner on a subset of two-thirds of the data, starting with a covariate-free model then progressing to a covariate model using the nonlinear-mixed effect methodology. The remaining one-third of the data were used to validate several sparse sampling designs. RESULTS: A linear three-compartment model characterized vinorelbine blood concentrations (n=1228). Two primary pharmacokinetic parameters (total clearance and volume of distribution) were related to various combinations of covariates. The relationship for total clearance (CLtotal (l h-1)=29.2xBSAx(1-0.0090 Plt)+6.7xWt/Crs) was dependent on the patient's body surface area (BSA), weight (Wt), serum creatinine (Crs) and platelet count before administration (Plt). The optimal limited sampling strategy consisted of a combination of three measured blood concentrations; the first immediately before the end of infusion or 20 min later, the second at either 1 h, 3 h or 6 h and the third at 24 h after drug administration. CONCLUSIONS: A population pharmacokinetic model and a limited sampling strategy for intravenous vinorelbine have been developed. This is the first population analysis performed on the basis of a large phase I database that has identified clinical covariates influencing the disposition of i.v. vinorelbine. The model can be used to obtain accurate Bayesian estimates of pharmacokinetic parameters in situations where extensive pharmacokinetic sampling is not feasable.     

利用蒙特卡洛模拟对不同体质量患者使用头孢菌素类药物预防外科手术部位感染的给药方案优化

目的: 应用蒙特卡洛模拟评价和优化不同体质量患者预防外科手术部位感染的头孢菌素类药物给药方案。方法: 使用临床常见的给药剂量, 以% fT＞4MIC为药动学/药效学(PK/PD) 目标, 选择群体药动学数据为PK参数, 通过比较目标菌种的累积反应分数(cumulative fraction of response, CFR), 评价疗效和优化出最佳给药方案。结果: 正常体质量患者使用头孢唑啉预防金黄色葡萄球菌, 在3 h内所有CFR＞90%;预防大肠埃希菌, 使用2 g在2 h内, 或3 g在3 h内有效。超正常体质量患者预防金黄色葡萄球菌, 使用2 g在2 h内CFR＞90%;预防大肠埃希菌, 使用3 g在2 h内CFR＞90%。1.5 g头孢呋辛在1 h内CFR＞90%。正常体质量患者使用3 g预防金黄色葡萄球菌, 大肠埃希菌和凝固酶阴性葡萄球菌时, 大部分能在2 h内达到有效预防效果。超正常体质量患者剂量为3 g, 预防金黄色葡萄球菌和凝固酶阴性葡萄球菌结果提示2 h内预防有效; 预防大肠埃希菌, 仅部分结果显示在1 h内CFR＞90%。结论: 头孢唑啉对不同体质量的患者给药方案不同, 正常体质量患者选择"2 g, q2 h"或"2 g, q3 h"的给药方案, 超正常体质量患者选择"3 g, q2 h"的给药方案。头孢呋辛对正常和超正常体质量患者均选择"3 g, q2 h"的方案。     

Performance of an Iterative Two-Stage Bayesian Technique for Population Pharmacokinetic Analysis of Rich Data Sets

Purpose To test the suitability of an Iterative Two-Stage Bayesian (ITSB) technique for population pharmacokinetic analysis of rich data sets, and to compare ITSB with Standard Two-Stage (STS) analysis and nonlinear Mixed Effect Modeling (MEM). Materials and Methods Data from a clinical study with rapacuronium and data generated by Monte Carlo simulation were analyzed by an ITSB technique described in literature, with some modifications, by STS, and by MEM (using NONMEM). The results were evaluated by comparing the mean error (accuracy) and root mean squared error (precision) of the estimated parameter values, their interindividual standard deviation, correlation coefficients, and residual standard deviation. In addition, the influence of initial estimates, number of subjects, number of measurements, and level of residual error on the performance of ITSB were investigated. Results ITSB yielded best results, and provided precise and virtually unbiased estimates of the population parameter means, interindividual variability, and residual standard deviation. The accuracy and precision of STS was poor, whereas ITSB performed better than MEM. Conclusions ITSB is a suitable technique for population pharmacokinetic analysis of rich data sets, and in the presented data set it is superior to STS and MEM. An erratum to this article can be found at     

有限采样策略应用于中国器官移植患者霉酚酸暴露量估算的研究进展

霉酚酸(mycophenolic acid,MPA)是一种抗代谢免疫抑制药,广泛应用于实体器官移植术后,其具有治疗窗窄、药动学个体差异大等特点,常常需要治疗药物监测(therapeutic drug monitoring,TDM)测定药-时曲线下面积(area under the concentration-time ...     

Nonlinear pharmacokinetics of piperacillin in healthy volunteers--implications for optimal dosage regimens

AIMS

(i) To describe the first-order and mixed-order elimination pathways of piperacillin, (ii) to determine the between occasion variability (BOV) of pharmacokinetic parameters and (iii) to propose optimized dosage regimens.

METHODS

We performed a five-period replicate dose study in four healthy volunteers. Each subject received 4 g piperacillin as a single 5 min intravenous infusion in each study period. Drug analysis was performed by HPLC. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and Monte Carlo simulation to predict the probability of target attainment (PTA) with a target time of non-protein bound concentration above MIC >50% of the dosing interval.

RESULTS

A model with first-order nonrenal elimination and parallel first-order and mixed-order renal elimination had the best predictive performance. For a 70 kg subject we estimated 4.40 l h⁻¹ for nonrenal clearance, 5.70 l h⁻¹ for first-order renal clearance, 170 mg h⁻¹ for V_max, and 49.7 mg l⁻¹ for K_m for the mixed-order renal elimination. The BOV was 39% for V_max, 117% for K_m, and 8.5% for total clearance. A 30 min infusion of 4 g every 6 h achieved robust (≥90%) PTAs for MICs ≤12 mg l⁻¹. As an alternative mode of administration, a 5 h infusion of 6 g every 8 h achieved robust PTAs for MICs ≤48 mg l⁻¹.

CONCLUSIONS

Part of the renal elimination of piperacillin is saturable at clinically used doses. The BOV of total clearance and volume of distribution were low. Prolonged infusions achieved better PTAs compared with shorter infusions at similar daily doses. This benefit was most pronounced for MICs between 12 and 48 mg l⁻¹.     

有限取样法估算中国成年肾移植受者霉酚酸血药浓度-时间曲线下面积

目的建立有限取样方法用于估算霉酚酸(MPA)(免疫抑制药)的AUC。方法31例成年肾移植受者按每次1g,每12h给药1次口服霉酚酸酯(MMF),用线性梯形法计算MPA AUC0-12h,进行相关分析,确定MPAAUC0-12h值的可预测时间点。进行多元线性回归,确定有限取样方案。结果MPAAUC0-12h与服药后0.5h(C0.5,γ=0.60)、1h(C1,γ=0.60)、4h(C4,γ=0.6121)和10h(C10,γ=0.6371)(均P<0.001)血药浓度有较好的相关性,MPAAUC=12.61 0.37C0.5 0.49C1 3.22C4 8.17C10;有84%(26/31)估算AUC误差在10%以内,有97%(30/31)估算AUC误差在20%以内。结论有限取样法可用于估算肾移植受者口服MMF后MPAAUC0-12h。     

用模型和模拟方法设计氨氯地平的群体药动学研究方案

合理的采样设计是建立可靠群体药动学模型的重要基础。应用非线性混合效应模型的群体药动学研究,是一种有效利用稀疏血样数据估算群体药动学参数的方法。本研究根据D最优化设计和贝叶斯法设计采样方案。以已报道的氨氯地平群体药动学模型为基础,根据临床研究的目的、给药方案和随访时间等设计几套采样方案,采用WinPOPT软件计算优化采样方案,用蒙特卡罗法(Monte Carlo)对各优化的采样方案分别建立一套含400个患者的NONMEM数据文件,用NONMEM7.2软件模拟氨氯地平的浓度数据,然后估算其重要药动学参数(CL/F,V/F和Ka),并计算其平均预测误差(MPE)和平均绝对预测误差(MAPE)。在6个采样方案中,以方案6和3对CL/F估算的准确度和精密度较优,MPE分别为0.1%和0.6%,MAPE均为0.7%。对V的估算,各采样方案间无明显差异。因此,选用氨氯地平拟合药动学参数的准确度和精密度较优,且采样点个数较少的方案3为最佳临床研究方案。本研究旨在为开展氨氯地平在肾功能损害合并高血压患者的群体药动学研究提供科学、有效的采样方法,为群体PK/PD研究提供一种优化设计临床研究方案的科学方法。     

哌拉西林他唑巴坦在肾内科患者中的群体药动学和蒙特卡罗模拟

目的:建立哌拉西林他唑巴坦在肾内科患者中的群体药动学模型,应用蒙特卡罗模拟优化其给药方案,以促进个体化给药.方法:采用高效液相色谱法测定50名肾内科患者静脉滴注哌拉西林-他唑巴坦的血清浓度310例次并收集相关临床指标,运用非线性混合效应模型(NONMEM)程序建立群体药动学模型.采用蒙特卡罗模拟(Monte Carlo simulation, MCS)比较哌拉西林他唑巴坦的不同给药方案对不同MIC群体的药效学目标到达.结果:哌拉西林、他唑巴坦的药动学符合一室模型,群体典型值及个体间差异(Between Subject Variability,BSV)分别为:哌拉西林CL/F=13.74 L·h^-1,BSV=11.1%;V/F=21.69 L,BSV=8.0%,他唑巴坦CL/F=9.32 L·h^-1, BSV=9.11%;V/F=16.0 L, BSV=5.28%;固定效应参数中,肌酐清除率对参数有影响.对于MIC值较大的细菌,延长输注的给药方案获得了更高的目标的累积反应分数(CFR).结论:群体药动学模型和蒙特卡罗模拟,可为调整哌拉西林他唑巴坦的治疗方案提供有效的分析手段.