成人肝移植术后他克莫司群体药动学研究

目的：应用非线性混和效应模型考察中国肝移植患者他克莫司群体药动学特征。方法：回顾收集天津市第一中心医院成人肝移患者57例,1 094个他克莫司谷浓度点,验证组患者10例,183个谷浓度点。采用一房室模型,分析处理数据,采用NPDE、Bootstrap和外部验证的方法对模型进行评估。结果：最终模型显示血红蛋白（HGB）和术后时间（POD）为影响清除率的主要因素。药动学参数的群体典型值：清除率（CL/F）估算值为19.8 L·h^-1,表观分布容积估算值为597 L。模型评价显示该模型及所估算参数稳定。结论：本研究所建立的成人肝移植受者口服他克莫司的群体药动学模型能较好地估算患者的个体及群体药动学参数,为今后肝移植患者个体化给药方案的制订提供相关参考。     

他克莫司在肝移植患者中群体药动学研究进展

新型强效免疫抑制剂广泛应用于肝移植术后受体患者。其中,他克莫司在临床的应用不仅预防和治疗了肝移植患者术后抗移植排斥反应,提高移植器官的存活率,并已成为肝移植术后抗排异反应的一线用药。本文从他克莫司及其在肝移植患者中的应用、群体药动学的基本认识,以及口服他克莫司在肝移植患者的群体药动学研究等方面做一综述。     

肝移植患者术后口服他克莫司群体药动学研究

目的:考察肝移植患者术后口服他克莫司的群体药动学模型,为临床个体化用药提供参考。方法:回顾性收集天津市第一中心医院18例肝移植患者术后口服他克莫司12 h全血药浓度监测数据145个。运用非线性混合效应模型(nonlinear mixed effect model,NONMEM)建立他克莫司群体药动学模型,并考察了年龄、性别、移植术后天数、血清肌酐等固定效应对药动学参数的影响,得到最终模型方程,最后利用Bayesian反馈得到的个体药动学参数值进行个体化给药方案设计。结果:本次研究建立起了口服他克莫司一级吸收和消除的二房室群体药动学模型,并通过NONMEM模拟程序为1例患者进行了个体化给药设计。结论:NONMEM法建立的模型能较好地估算他克莫司的个体及群体药动学参数,为临床合理使用他克莫司提供参考依据。     

他克莫司在肝移植患者体内的药动学

目的:考察口服他克莫司(FK506)胶囊在肝移植患者体内的药动学特征,为临床调整个体化给药方案提供科学依据.方法:22例肝移植患者,给予FK506为基础的免疫抑制治疗,术后24 h后开始服用FK506,剂量为(0.13±0.04)mg·kg-1·d-1,每12 h服用1次.受试者在服药前(0 h)和服药后0.33,0.66,1,1.5,2,3,4,6,8,10,12 h共12个时间点分别取外周静脉血,用MEIA法进行药物浓度测定,PKBP-N1软件计算药动学参数,并绘制血药浓度-时间曲线.结果:FK506口服后血药浓度一时间曲线为一级吸收二室开放模型,22例肝移植受者在口服FK506后,血药浓度迅速上升达到峰值,然后迅速下降,PK参数分别为t1/2a为(1.2±2.1)h,t1/2β(21.0±10.1)h,Ka(2.2±0.9)·h-1,CLs(0.64±0.3)L·h-1·kg-1,AUG0-12为(136.2±33.7)μg·h·L-1.本实验中和AUC相关性最好的是G、C4、C8,r分别为0.95,0.94,0.91.结论:肝移植患者口服FK506药动学个体差异大,用药应个体化.根据PKBP-N1分析得到的药动学参数,能较好的体现患者的药动学信息,根据单点血药浓度可以比较准确的预测AUC0-12.     

肾病综合征患者他克莫司的群体药动学研究

目的 应用非线性混合效应模型NONMEM考察成人肾病综合征患者他克莫司的群体药动学特征。方法 回顾性收集肾病综合征患者51例,246个血药浓度监测数据。以其年龄、性别、体质量、他克莫司日剂量、肝肾功能及合并用药等为协变量,采用具有一级吸收和消除的一室模型拟合数据,并通过自举法和正态化预测分布误差法对模型进行验证。结果 他克莫司的表观清除率（CL/F）为13.9 L·h^-1,表观分布容积（V/F）为382 L,他克莫司日剂量（DD,mg·d^-1）、红细胞压积（HCT）、合并使用五酯胶囊对CL/F有显著影响。模型评价显示该模型及参数估算值可靠稳定,CL/F的最终模型为CL/F=13.9×0.668^WZ×（DD/2）^0.354×（HCT/0.394）^-0.522,其中合并使用五酯胶囊时WZ为1,反之为0。结论 建立的肾病综合征患者口服他克莫司的群体药动学模型能较好地估算患者的群体及个体药动学参数,可为该药的个体化给药方案设计提供参考。     

他克莫司在儿童活体肝移植中应用及药代动力学特点研究进展

活体肝移植目前是治疗儿童终末期肝病的有效治疗手段.由于儿童正处于生长发育期,特别是婴幼儿在解剖、生理特点及对药物反应性及耐受性方面都与成人有很大差异,药物代谢酶系统、肝肾解毒排毒功能发育尚不健全,导致药物在体内吸收、分布、代谢、排泄以及药效学都有显著的特异性.目前应用广泛的免疫抑制剂为他克莫司(Tacroli-mus,FK506),但他克莫司的治疗窗较窄,血药浓度过高或过低容易出现毒副作用或治疗效果不佳甚至导致排斥反应的发生,特别是儿童这一特殊群体应用更需注意.本文就他克莫司在儿童活体肝移植中应用及药代动力学特点相关情况进行综述.     

肝移植患者他克莫司个体化给药研究

目的:建立人工神经网络用于估算他克莫司血药浓度.方法:收集26例肝移植患者口服他克莫司的94份全血浓度数据,采用遗传算法配合动量法优化网络参数,建立人工神经网络.结果:人工神经网络平均预测误差(MPE)与平均绝对预测误差( MAE)分别为(-0.11±2.81) ng/mL和(2.14±1.72) ng/mL,78.6％血药浓度数据绝对预测误差≤3.0 ng/mL.多元线性回归 MPE与 MAE分别为(0.56±2.70) ng/mL和(2.15±1.63) ng/mL,9例次(9/14,64.3％)绝对预测误差≤3.0 ng/mL.人工神经网络准确性及精密度优于多元线性回归.结论:人工神经网络预测可用于预测他克莫司血药浓度,指导个体化给药.     

成人慢性肾小球肾炎患者他克莫司群体药动学研究

目的:建立成人慢性肾小球肾炎患者他克莫司群体药动学(population pharmaco-kinetics,PPK)模型。方法:收集55例慢性肾小球肾炎患者的268个他克莫司血药浓度数据。采用非线性混合效应模型考察CYP3A5基因型、体质量、年龄、实验室指标、合并用药等对他克莫司药动学参数的影响,建立他克莫司PPK模型,并通过拟合优度诊断、Bootstrap自举法及正态预测分布误差法对模型进行验证。结果:他克莫司表观清除率及表观分布容积的群体典型值分别为13.8L·h-1和733L,CYP3A5基因型和合并用药五酯胶囊对他克莫司清除率具有显著影响。经验证他克莫司PPK模型稳定有效。结论:首次建立成人慢性肾小球肾炎患者他克莫司PPK模型,可为慢性肾小球肾炎患者的他克莫司个体化给药提供参考。     

调整给药方案对他克莫司低谷浓度肝移植患者的影响

目的:研究他克莫司在低谷浓度肝移植患者的药动学,并在每天总药量不增加的前提下,调整给药方案,使患者的谷浓度达到有效浓度范围。方法:对6例低谷浓度的肝移植患者进行药动学研究,将每12小时给药1次改为每8小时给药。采用微粒子酶免疫分析法(MEIA)测定血药浓度,比较给药方案调整前、后他克莫司谷浓度。结果:调整后的他克莫司平均谷浓度高于调整前的谷浓度(P<0.05),他克莫司的平均谷浓度由调整前的5.8μg.L-1升至调整后的7.8μg.L-1,升高了23.3%。结论:对于他克莫司低谷浓度的肝移植患者,在不增加日给药剂量的前提下,可以通过缩短给药间隔增加谷浓度,使血药浓度更加平稳。     

全量采样的他克莫司群体药代动力学分析

目的:分析中国人他克莫司口服给药的群体药代动力学特征,比较不同用药人群的药代动力学差异.方法:收集健康受试者和肝脏移植患者的他克莫司全量采样药物浓度数据,用非线性混合效应模型(NONMEM)进行群体分析,建立二房室药代动力学模型,个体间变异用指数模型,残差变异用常系数模型,考察吸收速率常数(Ka)、中央室清除率(CL)、中央室分布容积(V2)、室间清除率(Q)、外周室分布容积(V3)等参数在不同组间的差异.通过自举验证、拟合优度、直观预测检验(VPC)来评价最终模型的拟合性能.结果:K3、CL、V2、Q、V3的群体典型值分别是1.09h-1、19.9L·h-1、10.1×(1+CENT×2.34)L、24.8×(1 +CENT× 1.69)L·h-1、353 L,单剂量时ALAG是0.258,个体间变异系数分别是30.2％、71.8％、131％、42.9％、59.7％,不同分析测试方法的残差变异系数分别是8.45％、34.4％,最终模型表明肝脏移植患者的V2和Q比健康受试者的高出2.34和1.69倍.最终模型能较好地预测他克莫司的浓度,浓度观察值(DV)与个体预测值(IPRED)的决定系数R2＝0.82.结论:自举验证、拟合优度评价结果都表明模型稳定,预测性可靠.他克莫司口服给药符合二房室特征,体重对各参数没有显著性影响,肝脏移植患者的V2和Q明显高于健康人群.结果提示不同人群的他克莫司体内药代动力学过程不完全相同.     

Initial dosage optimization of tacrolimus in Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics

ABSTRACT

Background

The purpose of our research was to recommend the initial tacrolimus dosage for Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics.     

他克莫司基因组学在肝移植的应用及其研究进展

他克莫司是一种新型强效免疫抑制剂,在临床广泛应用于肝移植等器官移植术后的抗排异治疗。在肝移植人群中,他克莫司的药代动力学及血药浓度存在个体差异,其用药的个体差异与细胞色素P450酶系CYP3A5和P糖蛋白的基因多态性之间存在较密切联系。本文对他克莫司的药效学、药代动力学、血药浓度范围及其药物基因组学的研究进展进行了综述。     

Population pharmacokinetics of tacrolimus in Asian paediatric liver transplant patients

AIMS: The purpose of this study was to describe the population pharmacokinetics of intravenous and oral tacrolimus (FK506) in 20 Asian paediatric patients, aged 1-14 years, following liver transplantation and to identify possible relationships between clinical covariates and population parameter estimates. METHODS: Details of drug dosage histories, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring data accumulated for at least 4 days after surgery. Before analysis, patients were randomly allocated to either the population data set (n = 16) or a validation data set (n = 4). The population data set was comprised of 771 concentration measurements of patients admitted over the last 3 years. Population modelling using the nonlinear mixed-effects model (NONMEM) program was performed on the population data set, using a one-compartment model with first-order absorption and elimination. Population average parameter estimates of clearance (CL), volume of distribution (V) and oral bioavailability (F) were sought; a number of clinical and demographic variables were tested for their influence on these parameters. RESULTS: The final optimal population models related clearance to age, volume of distribution to body surface area and bioavailability to body weight and total bilirubin concentration. Predictive performance of this model evaluated using the validation data set, which comprised 86 concentrations, showed insignificant bias between observed and model-predicted blood tacrolimus concentrations. A final analysis performed in all 20 patients identified the following relationships: CL (l h-1) = 1.46 *[1 + 0. 339 * (AGE (years) -2.25)]; V (l) = 39.1 *[1 + 4.57 * (BSA (m2)-0. 49)]; F = 0.197 *[1 + 0.0887 * (WT (kg) -11.4)] and F = 0.197 *[1 + 0.0887 * (WT (kg) -11.4)] * [1.61], if the total bilirubin > or = 200 micromol l-1. The interpatient variabilities (CV%) in CL, V and F were 33.5%, 33.0% and 24.1%, respectively. The intrapatient variability (s.d.) among observed and model-predicted blood concentrations was 5.79 ng ml-1. CONCLUSIONS: In this study, the estimates of the pharmacokinetic parameters of tacrolimus agreed with those obtained from conventional pharmacokinetic studies. It also identified significant relationships in Asian paediatric liver transplant patients between the pharmacokinetics of tacrolimus and developmental characteristics of the patients.     

Population pharmacokinetics and Bayesian estimation of tacrolimus exposure in paediatric liver transplant recipients

Aims

The objectives of this study were to develop a population pharmacokinetic (PopPK) model for tacrolimus in paediatric liver transplant patients and determine optimal sampling strategies to estimate tacrolimus exposure accurately.

Methods

Twelve hour intensive pharmacokinetic profiles from 30 patients (age 0.4–18.4 years) receiving tacrolimus orally were analysed. The PopPK model explored the following covariates: weight, age, sex, type of transplant, age of liver donor, liver function tests, albumin, haematocrit, drug interactions, drug formulation and time post-transplantation. Optimal sampling strategies were developed and validated with jackknife.

Results

A two-compartment model with first-order absorption and elimination and lag time described the data. Weight was included on all pharmacokinetic parameters. Typical apparent clearance and central volume of distribution were 12.1 l h⁻¹ and 31.3 l, respectively. The PopPK approach led to the development of optimal sampling strategies, which allowed estimation of tacrolimus pharmacokinetics and area under the concentration–time curve (AUC) on the basis of practical sampling schedules (three or four sampling times within 4 h) with clinically acceptable prediction error limit. The mean bias and precision of the Bayesian vs. reference (trapezoidal) AUCs ranged from −2.8 to −1.9% and from 7.4 to 12.5%, respectively.

Conclusions

The PopPK of tacrolimus and empirical Bayesian estimates represent an accurate and convenient method to predict tacrolimus AUC_(0–12) in paediatric liver transplant recipients, despite high between-subject variability in pharmacokinetics and patient demographics. The developed optimal sampling strategies will allow the undertaking of prospective trials to define the tacrolimus AUC-based therapeutic window and dosing guidelines in this population.     

五酯胶囊对肝移植受者他克莫司浓度的影响

目的评价五酯胶囊对肝移植受者术后服用他克莫司血药浓度的影响。方法选取60例肝移植受者,随机分成2组,试验组32例,口服他克莫司的同时,加服五酯胶囊;对照组28例,服用他克莫司,未服五酯胶囊,连续服药6个月,比较2组他克莫司的用量、血药浓度及肝肾功能生化指标。结果服用五酯胶囊后,试验组他克莫司血药浓度升高,相应减少服用量,试验组每日服用他克莫司剂量比对照组显著降低(P<0.01);但术后1,2,3,4,6月复查,2组他克莫司血药浓度及肾功能(Cr)无明显差异(P>0.05);试验组与对照组比较,肝功能(ALT)有所改善,差异有统计学意义(P<0.05)。结论五酯胶囊能明显提高肝移植受者他克莫司全血浓度,同时减少他克莫司服用量,降低患者医疗费用。     

A population pharmacokinetic study of tacrolimus in healthy Chinese volunteers and liver transplant patients

Aim:

To develop a population pharmacokinetic (PopPK) model of tacrolimus in healthy Chinese volunteers and liver transplant recipients for investigating the difference between the populations, and for potential individualized medication.

Methods:

A set of 1100 sparse trough concentration data points from 112 orthotopic liver transplant recipients, as well as 851 dense data points from 40 healthy volunteers receiving a single dose of tacrolimus (2 mg, po) were collected. PopPK model of tacrolimus was constructed using the program NONMEM. Related covariates such as age, hepatic and renal functions that were potentially associated with tacrolimus disposition were evaluated. The final model was validated using bootstrapping and a visual predictive check.

Results:

A two-compartment model of tacrolimus could best describe the data from the two populations. The final model including two covariates, population (liver transplant recipients or volunteers) and serum ALT (alanine aminotransferase) level, was verified and adequately described the pharmacokinetic characteristics of tacrolimus. The estimates of V2/F, Q/F and V3/F were 22.7 L, 76.3 L/h and 916 L, respectively. The estimated CL/F in the volunteers and liver transplant recipients was 32.8 and 18.4 L/h, respectively. Serum ALT level was inversely related to CL/F, whereas age did not influence CL/F. Thus, the elderly (≥65 years) and adult (<65 years) groups in the liver transplant recipients showed no significant difference in the clearance of tacrolimus.

Conclusion:

Compared with using the sparse data only, the integrating modeling technique combining sparse data from the patients and dense data from the healthy volunteers improved the PopPK analysis of tacrolimus.     

肝移植术后他克莫司加泼尼松免疫抑制治疗的临床疗效

目的 :探讨肝移植术后他克莫司 (FK5 0 6 ) +泼尼松 (Pred)二联免疫抑制治疗方案的临床疗效及药物不良反应。方法 :对肝移植术后应用FK5 0 6 +Pred二联免疫抑制方案治疗的 2 5例患者 (A组 ,术后 2 4h即应用FK5 0 6 +Pred方案的 15例 ,以及因出现排斥反应或严重药物不良反应由CsA +MMF +Pred改为FK5 0 6 +Pred方案的 10例 )和应用环孢素 (CsA) +霉酚酸酯(MMF) +Pred三联免疫抑制方案治疗的 2 0例患者 (B组 )进行比较 ,临床观察 12mo。结果 :2组移植前后血Cr均无明显变化 ,但A组移植术后排斥反应及药物不良反应发生率显著低于B组 (P <0 0 1) ;由CsA +MMF +Pred改为FK5 0 6 +Pred方案的 10例患者 ,排斥反应和药物不良反应均得到有效控制。A组的主要药物不良反应有腹泻和神经系统毒性 ,仅有 2例分别于术后mo 1,2发生血糖升高。结论 :肝移植术后FK5 0 6 +Pred二联免疫抑制治疗方案是有效的     

Dosing recommendations based on population pharmacokinetics of tacrolimus in Mexican adult patients with kidney transplant

The aim of this study was to perform a population pharmacokinetic analysis of tacrolimus in Mexican adult kidney transplant patients to analyse the influence of clinical and genetic covariates to propose a dosage regimen. Kidney transplant patients (>18 years old) receiving oral tacrolimus treatment were included in the current study. The population pharmacokinetic model was built using a one‐compartment model and the First Order Conditional Estimation method with Interaction (FOCEI via NONMEM v.7.3.). A total of 600 tacrolimus trough blood concentrations from 52 kidney transplant patients were analysed. Tacrolimus clearances were 26, 18.8 and 12.3 L/h, for patients with genetic polymorphisms CYP3A5*1*1, *1*3 and *3*3, respectively. The influence of haematocrit was inversely related to tacrolimus clearance, following an allometric power function. Total volume of distribution was 604 L. Interindividual variability associated with tacrolimus clearance and distribution volume for the final model was 33 and 63%, respectively, with a residual error of 2.5 ng/mL. Relative bioavailability was calculated between generic formulations A (0.53) and B (1) of tacrolimus. Internal validation was performed through bootstrap analysis to evaluate the stability of the final model; external validation was performed in a new group of patients (n = 13) to estimate residual errors on basic (57.8%) and final (34.8%) models. Finally, stochastic simulations were performed to propose a dosage regimen based on haematocrit, CYP3A5 genotype and generic formulation of tacrolimus. A stable and predictive population pharmacokinetic model of tacrolimus was developed for Mexican adult kidney transplant patients; additionally, the proposed dosage regimen of tacrolimus should be prospectively validated.     

Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients

What is already known about this subject

• In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability.
• Some studies of population pharmacokinetics have already been conducted in liver transplant recipients and in paediatric patients.

What this study adds

• Our work determined population pharmacokinetic parameters, in particular bioavailability, in kidney transplant recipients and the relative importance of factors influencing the disposition of tacrolimus.
• Clearance was modelled and days postoperation and corticosteroids dose were significant covariates.

Aims

The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics.

Methods

The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring.

Results

A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 ± 0.2 l h⁻¹. Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 ± 0.5 days, with a maximal value of 5.6 l h⁻¹. Moreover clearance increased by approximately 1.6 fold (range 0.5–1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 ± 13 l kg⁻¹) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F.

Conclusions

The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance.