皖南地区汉族人群华法林稳定剂量模型预测准确性的评价与建立

目的:比较并评价4种华法林稳定剂量预测模型的预测准确性并建立华法林剂量预测模型。方法:收集483名服用华法林患者的临床资料,检测患者CYP2C9*3和VKORC1基因型,以预测百分比和平均绝对误差分析4种华法林稳定剂量预测模型的准确性;将纳入影响华法林稳定剂量的相关因素进行多元线性回归分析,得到相应的剂量预测模型。结果:CYP2C9*3/*3型患者华法林稳定剂量为(0.83±0.19) mg·d^-1,显著低于*1/*1型和*1/*3型患者(P<0.05),VKORC1 GG型患者华法林稳定剂量为(4.17±1.49) mg·d^-1,显著高于AA型和GA型患者(P<0.05);4种华法林剂量预测模型的预测剂量与实际剂量差异均显著相关(P<0.01),IWPC模型的相关性最好,r=0.519;MAE最低的是TAN模型,为(0.70±0.53) mg·d^-1,指南模型的MAE最高,为(0.86±0.60) mg·d^-1;华法林稳定剂量模型建立结果D(mg·d^-1)=...     

山西人群华法林基因多态性与其稳定剂量预测模型的研究

目的 建立适合山西人群的华法林稳定剂量预测模型。方法 选取符合入组标准的山西籍汉族患者,采用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)技术检测基因VKOR复合体(VKORC1)、细胞色素P450(CYP)2C9、γ-谷氨酰羧化酶(GGCX)、环氧化物水解酶(EPHX1)多态性。记录患者临床信息,采用逐步多元回归分析法计算华法林稳定剂量预测模型公式。结果 华法林稳定剂量预测模型包括VKORC1、CYP2C9、GGCX、EPHX1及患者的身高等因素(R²=0.284);在模型中加入GGCX、EPHX1基因型后,模型的总体R²从0.257提升至0.284,GGCX、EPHX1基因型在模型中解释了2.7%的剂量差异。维生素K的日均摄入量未对华法林稳定剂量有显著影响,但是男性每天维生素K摄入量明显低于女性。将服用华法林患者国际标准化比值(INR)值分为低INR值组、正常组、高INR值组,显示随着INR值升高,患者日均维生素K摄入量降低。结论 基于6种基因多态性的剂量预测模型可以帮助预测山西汉族患者华法林稳定剂量。     

基于Warfarindosing网站预测汉族人群华法林给药剂量与实际剂量的相关性研究

目的考察基于Warfarindosing网站预测汉族人群华法林剂量与实际剂量的相关性。方法选取某院2017年7月至2018年11月住院期间行华法林基因检测的108例汉族患者,记录其基本信息和华法林等用药情况,利用原位杂交荧光染色DNA测序的方法检测CYP2C9*3和VKORC1(-1639G>A)的基因型,并应用Warfarindosing网站预测患者华法林剂量,比较预测剂量与实际剂量差异。结果行基因检测的108例汉族患者中,以CYP2C9*1/*1 VKORC1AA基因型为主(71.30%),其次为CYP2C9*1/*1 VKORC1GA基因型(19.44%)。47例患者服用华法林,其中CYP2C9*1/*1 VKORC1 AA型患者实际剂量在预测剂量范围内的比例为82.85%(29/35),高于CYP2C9*1/*1 VKORC1 GA型患者实际初始剂量在预测剂量范围内的比例70.00%(7/10)。在院INR达标的23例患者中,CYP2C9*1/*1 VKORC1 AA型和CYP2C9*1/*1 VKORC1 GA型预测周剂量分别为(21.37±5.15)、(31.73±8.85)mg,实际维持周剂量分别为(21.29±6.26)、(27.00±6.00)mg,CYP2C9*1/*1 VKORC1 AA型预测的维持周剂量与实际维持周剂量差异无统计学意义,而CYP2C9*1/*1 VKORC1 GA型预测的维持周剂量显著大于实际维持周剂量。结论基于Warfarindosing网站预测汉族人华法林用药剂量具有一定的参考价值,可适用于汉族人群,尤其对CYP2C9*1/*1 VKORC1 AA型汉族患者华法林的周剂量预测准确性较高,具有较大的临床参考意义;但对于汉族CYP2C9*1/*1 VKORC1 GA基因型患者华法林的剂量预测亦存在局限性,有待于进一步临床研究。     

三种华法林基因预测模型与心脏瓣膜置换术后华法林剂量的相关性研究

目的 研究湖北地区汉族人细胞色素P450 (CYP) 2C9基因和维生素K环氧化物还原酶复合体1(VKORC1)基因型;评估3种不同华法林剂量预测模型与其剂量的相关性.方法 收集我院收治的心脏瓣膜置膜术后应用华法林的108例患者并获取华法林稳态剂量,采用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)技术检测CYP2C9和VKORC1基因型.比较3种基因预测模型结果与实际华法林稳态剂量的相关性.结果 根据基因型判断的华法林用药剂量与稳态剂量相关性更大,同时预测模型3相关性略高于预测模型2.结论 在湖北地区汉族人群中,存在CYP2C9和VKORC1基因多态性,且不同基因型患者华法林用量存在差异,预测模型有助于预测华法林稳态剂量.     

3厂家华法林钠片分剂量的评价

目的:评价3厂家华法林钠片分剂量的合理性。方法:对A(进口,未包衣)、B(国产,糖衣片)、C(国产,薄膜衣片)厂家的华法林钠片进行分剂量,分别由1名学生用切药器、剪刀、小刀将整片进行二、四等分;由另外2名学生用剪刀和2名药师用磨粉分包将整片进行三、五等分(n=30)。参照《欧洲药典》第6版,对二、四等分片进行分剂量准确性评价,对二、三、四、五等分片进行等分片脆碎度评价,并考察3厂家片剂的崩解时限。结果:3厂家二、三、四、五等分分剂量准确性均不符合《欧洲药典》规定。3种方法二、四等分分剂量合格率无明显差异,2名学生(除五等分外)间比较、2名药师间比较分剂量合格率均无明显差异。仅A厂家片剂的等分片脆碎度符合规定,B、C厂家片剂3种方法分剂量的等分片脆碎度均不符合规定。A、B、C厂家片剂的崩解时限分别为3、29、23min。结论:3厂家的华法林钠片均不适合用切药器、剪刀、小刀或磨粉分包分剂量。     

基于基因多态性建立肾功能不全患者华法林稳态剂量的预测模型

目的:基于CYP2C9*3(1075A>C)和VKORC1-1639G>A基因多态性,建立肾功能不全患者华法林稳态剂量的预测模型。方法:收集2016年6月-2018年6月西安交通大学第一附属医院肾脏内科服用华法林的肾功能不全患者(涉及疾病包括原发性肾小球肾炎、慢性肾盂肾炎、高血压肾小动脉硬化、糖尿病肾病、继发性肾小球肾炎、肾小管间质病变、遗传性肾脏疾病)且国际标准化比值(INR)在1.5～3.0的103例患者的临床资料,采用荧光染色原位杂交法检测CYP2C9*3(1075A>C)和VKORC1-1639G>A基因型,分析患者基因型、性别、年龄、体质量指数(BMI)、肾小球滤过率(eGFR)与华法林稳态剂量的相关性,采用多元线性回归方法建立肾功能不全患者华法林稳态剂量的预测模型,并另选25例患者进行验证。结果:103例患者的CYP2C9*3(1075A>C)和VKORC1-1639G>A基因频率均符合Hardy-Weinberg平衡,其中CYP2C9*3(1075A>C)AA基因型患者华法林平均稳态剂量(3.20±0.88)mg/d显著高于CYP2C9*3(1075A>C)AC基因型患者华法林平均稳态剂量(2.17±0.13)mg/d(P<0.05),VKORC1-1639G>A AA基因型患者华法林平均稳态剂量(2.89±0.08)mg/d显著低于VKORC1-1639G>A GA基因型患者华法林平均稳态剂量(4.01±0.17)mg/d(P<0.05);男性患者华法林稳态剂量(3.16±0.11)mg/d高于女性患者华法林稳态剂量(3.07±0.13)mg/d(P>0.05);年龄与华法林稳态剂量呈负相关(P<0.05);eGFR与华法林稳态剂量呈正相关(P<0.05);BMI与华法林稳态剂量无明显相关性(P>0.05),肾功能不全患者华法林稳态剂量=3.057-0.73~*VKORC1-1639G>A+0.08~*eGFR-0.013~*年龄+0.565~*CYP2C9*3(1075A>C)[VKORC1-1639G>A:AA=1,GA=0,GG=0;CYP2C9*3(1075A>C):AA=1,AC=0;年龄为岁;eGFR单位为mL/(min·1.73 m~2)](R~2=0.502)。25例验证患者的预测模型剂量(3.12±0.56)mg/d与实际稳态剂量(3.06±0.93)mg/d差异无统计学意义(P>0.05)。结论:CYP2C9*3(1075A>C)AA和VKORC1-1639 G>A不同基因型患者的华法林稳态剂量有明显差异,成功建立肾功能不全患者华法林稳态剂量的预测模型。     

载脂蛋白E基因多态性对中国人群华法林维持剂量影响的meta分析

目的 系统评价载脂蛋白E （apolipoprotein E,APOE）基因多态性与中国人群华法林维持剂量的关系。方法 计算机检索PubMed、EMBase、Cochrane图书馆、CNKI和万方数据库,收集中国人群APOE基因多态性与华法林维持剂量关系的研究,提取资料并评价文献质量,采用RevMan 5.3统计软件进行meta分析。结果 共纳入11项研究,2 320例患者。Meta分析结果显示,APOE E2（E2/E2,E2/E3）基因型华法林维持剂量比APOE E3（E3/E3）基因型高30%,APOE E2（E2/E2,E2/E3）基因型华法林维持剂量比APOE E4（E3/E4,E4/E4）基因型高43%,差异均具有统计学意义,APOE rs7412 TT基因型所需华法林维持剂量明显低于CC及CT基因型（P<0.05）。结论 中国人群APOE E2（E2/E2,E2/E3）基因型所需华法林维持剂量显著增高,APOE rs7412 TT基因型所需华法林维持剂量明显降低。     

基因多态性与华法林的起始给药剂量的相关性研究

目的:探讨CYP2C9与VKORC1基因多态性对于个体华法林的起始给药剂量的影响,为临床个体化使用华法林提供实验依据。方法:选取某院2014年1月~2016年1月收治的232例心血管疾病患者,平均分为对照组和观察组。对照组采取常规华法林治疗模式,观察组通过基因测序法检测116例患者CYP2C9、VKORC1基因多态性后,分基因型个性化用药,检测不同给药剂量的INR值,统计并分析两组之间的华法林起始给药剂量、治疗效果及不良事件的发生率。结果:相比于对照组,观察组的华法林起始剂量降低,具有统计学差异(P0.05);不良反应发生率明显减少。结论:在个体化使用华法林的临床疗效中,CYP2C9和VKORC1基因与相应华法林的起始给药剂量及最终治疗疗效存在着密不可分的联系,对心血管疾病给药剂量具有重要性。     

基于临床参考及基因因素建立华法林稳定维持剂量预测模型

目的 探讨华法林应用的临床参考因素及基因因素与华法林稳定维持剂量的相关性,并尝试构建适用于非瓣膜病心房纤颤（non-valvular-disease atrial fibrillation,NVAF）患者华法林稳定维持剂量的预测模型。方法 按照纳入标准共纳入126例患者,应用测序反应通用试剂盒及荧光检测仪检测细胞色素P450 2C9和维生素K环氧化物还原酶基因多态性,同时记录华法林应用的临床参考因素：年龄、体质量、房颤栓塞风险评分系统（CHA₂DS₂-VASc）评分、房颤出血风险评分系统（HAS-BLED）评分、谷丙转氨酶（glutamic-pyruvic transaminase,ALT）、肾小球滤过率（glomerular filtration rate,GFR）、左心室射血分数（left ventricular ejection fraction,LVEF）、二尖瓣环水平左室侧壁组织多普勒S波;采用相关性分析探讨临床参考因素及基因多态性与华法林稳定维持剂量的相关性,并通过多元线性回归建立了华法林稳定维持剂量预测模型。结果 体质量、ALT水平、二尖瓣环水平左室侧壁组织多普勒S波与华法林稳定维持剂量成正相关,年龄、CHA₂DS₂-VASc评分、HAS-BLED评分则成负相关,而LVEF、GFR未显示明显的相关性。建立的预测模型对已有样本验证准确率达55.6%。结论 该模型可用于预测NVAF患者华法林稳定维持剂量。     

基因检测预测华法林给药剂量准确性的研究

目的：考察华法林IWPC预测剂量与实际剂量的相关性。方法：选取某院2014年11月至2015年8月间住院期间行华法林基因检测的患者97例,记录其基本信息和临床用药情况,利用基因测序的方法检测CYP2C9*2,*3和VKORC1 G>A基因型,并利用IWPC公式预测患者华法林剂量,考察预测剂量与实际剂量相关性。结果：行基因检测的97例患者中,73例服用华法林,42例住院期间INR达标。初始预测剂量中,CYP2C9*3 AA/VKORC1 AA型实际初始剂量在预测剂量范围内的比例为81.13%（43/53例）,CYP2C9*3 AC/VKORC1 AA型实际初始剂量在预测剂量范围内的比例为62.50%（5/8例）,其余的基因型实际初始剂量在预测剂量范围内的比例较小。维持剂量中,预测周剂量的平均值为19.286 mg,实际维持周剂量平均值为19.958 mg,R=0.415,P=0.562>0.05,预测的维持周剂量与实际维持周剂量无显著差异,且VKORC1 AA/CYP2C9*3 AC和VKORC1 AG/CYP2C9*3 AA 2组中预测剂量与实际剂量相关系数分别为0.537和0.916,相关性良好。结论：基因检测预测华法林用药剂量具有一定的准确性,在初始剂量预测中,CYP2C9*3 AA/VKORC1 AA型和CYP2C9*3 AC/VKORC1 AA型预测准确性较高;维持剂量预测中,CYP2C9*3 AC/VKORC1 AA和CYP2C9*3 AA/VKORC1 AG预测准确性较高,具有较高临床参考意义。     

基于群体药动学模型的万古霉素个体化给药软件研制及应用

目的:研发基于建立的成人和老年群体药动学(population pharmacokinetics,PPK)模型的万古霉素(vancomycin,VCM)个体化给药软件。方法:根据已建立的成人和老年VCM的PPK模型信息,运用MyEclipse、SQL Server、JRE等工具软件研发VCM给药软件。软件开发方案包括需求分析,概要设计,详细设计,软件编码,软件测试以及软件维护和二次开发。结果:研制的VCM给药软件可实现感染患者信息输入和管理,软件通过接口调用非线性混合效应模型(NONMEM)软件,不仅能预测多种具体VCM给药方案下的血药浓度,供临床医师制定初始用药方案参考,而且能结合已有的血药浓度监测信息和贝叶斯反馈法更精准地预测血药浓度,辅助临床医师进一步优化给药方案。软件应用于VCM血药浓度解读,药师向临床做出剂量调整建议。采纳建议组患者复查的血药浓度均达到目标血药浓度范围。结论:本研究基于VCM的PPK模型研制的给药软件能快速方便地辅助成人和老年感染患者VCM的个体化给药。     

哮喘维持治疗中的可调节剂量与固定剂量疗法的研究进展

可调节维持剂量方案是近几年提出用于哮喘维持治疗的一种新的措施,与传统的固定剂量的治疗方案有很大的不同,也由此引发了很多争议。本文就这2种治疗方案比较的临床试验进行综述。     

External evaluation of population pharmacokinetic models of vancomycin in neonates: the transferability of published models to different clinical settings

Aims

Vancomycin is one of the most evaluated antibiotics in neonates using modeling and simulation approaches. However no clear consensus on optimal dosing has been achieved. The objective of the present study was to perform an external evaluation of published models, in order to test their predictive performances in an independent dataset and to identify the possible study-related factors influencing the transferability of pharmacokinetic models to different clinical settings.

Method

Published neonatal vancomycin pharmacokinetic models were screened from the literature. The predictive performance of six models was evaluated using an independent dataset (112 concentrations from 78 neonates). The evaluation procedures used simulation-based diagnostics [visual predictive check (VPC) and normalized prediction distribution errors (NPDE)].

Results

Differences in predictive performances of models for vancomycin pharmacokinetics in neonates were found. The mean of NPDE for six evaluated models were 1.35, −0.22, −0.36, 0.24, 0.66 and 0.48, respectively. These differences were explained, at least partly, by taking into account the method used to measure serum creatinine concentrations. The adult conversion factor of 1.3 (enzymatic to Jaffé) was tested with an improvement in the VPC and NPDE, but it still needs to be evaluated and validated in neonates. Differences were also identified between analytical methods for vancomycin.

Conclusion

The importance of analytical techniques for serum creatinine concentrations and vancomycin as predictors of vancomycin concentrations in neonates have been confirmed. Dosage individualization of vancomycin in neonates should consider not only patients'' characteristics and clinical conditions, but also the methods used to measure serum creatinine and vancomycin.     

中国汉族人群hGSTA1基因C-69T多态性分析

目的　研究中国汉族人群中人谷胱甘肽S 转移酶(hGSTA1 )C-69T基因多态性的分布。方法1 4 0例血样本来自中国2 5个省份的汉族人口,用聚合酶链反应 限制性片段长度多态性方法检测hGSTA1 69位点的变异。结果　中国汉族人群GSTA1基因 69位点的野生型纯合子(CC)基因型的分布频率为75 .0 %,突变型纯合子(TT)基因型为0 .7%,杂合子(CT)基因型为2 4 .3 %;C及T两种等位基因的频率分别为87.1 %及1 2 .9%。结论中国汉族人群GSTA1基因呈多态性分布,其等位基因和基因型频率不同于其他种族     

Evaluation of population pharmacokinetic models for amikacin dosage individualization in critically ill patients

Objectives The aim of this study was to evaluate the reliability for dosage individualization and Bayesian adaptive control of several literature‐retrieved amikacin population pharmacokinetic models in patients who were critically ill. Methods Four population pharmacokinetic models, three of them customized for critically‐ill patients, were applied using pharmacokinetic software to fifty‐one adult patients on conventional amikacin therapy admitted to the intensive care unit. An estimation of patient‐specific pharmacokinetic parameters for each model was obtained by retrospective analysis of the amikacin serum concentrations measured (n = 162) and different clinical covariates. The model performance for a priori estimation of the area under the serum concentration‐time curve (AUC) and maximum serum drug concentration (C_max) targets was obtained. Key findings Our results provided valuable confirmation of the clinical importance of the choice of population pharmacokinetic models when selecting amikacin dosages for patients who are critically ill. Significant differences in model performance were especially evident when only information concerning clinical covariates was used for dosage individualization and over the two most critical determinants of clinical efficacy of amikacin i.e. the AUC and C_max values. Conclusions Only a single amikacin serum level seemed necessary to diminish the influence of population model on dosage individualization.     

A minimax approach to the single-point method of drug dosing

The single-point dose prediction method is based on the observation that for drugs obeying single compartment elimination kinetics there is a nearly constant reciprocal relation between the plasma level at a fixed time following a single loading dose and the dose that is required to maintain the desired steady state plasma level of the drug. This paper describes an improved method for choosing a plasma sampling time and a proportionality constant. It applies to either drugs administered intravenously or to drugs whose rates of absorption from the site of administration are very rapid compared to their rates of elimination from the body. The sampling time and proportionality constant chosen are those that minimize the maximum relative deviation of the maintenance dose estimated by the single-point method from the dose that would be estimated if the individual's true elimination rate constant were known. The paper also supplies a method to determine the maximum error that may be introduced into the estimation of the maintenance dose by using the single-point method.This investigation was supported in part by NIH National Research Service Award GM 09279-02 (M.M.B.), NIH grant R01 AM 25744-07, and NATO Collaborative Research Grant 85/0207 (E.M.L.). M.M.B. is a Daland Scholar of the American Philosophical Society.     

Polymorphisms of genes in nitric oxide-forming pathway associated with ischemic stroke in Chinese Han population

Aim:

To investigate the association of polymorphisms in four critical genes implicated in the NO-forming pathway with ischemic stroke (IS) in a Chinese Han population.

Methods:

DNA samples of 558 IS patients and 557 healthy controls from Chinese Han population were genotyped using the Taqman^TM 7900HT Sequence Detection System. Six SNPs (rs841, rs1049255, rs2297518, rs1799983, rs2020744, rs4673) of the 4 related genes (eNOS, iNOS, GCH1, and CYBA) in the NO forming pathway were analyzed using the SPSS 13.0 software package for Windows.

Results:

One SNP located in the intron of GCH1 (rs841) was associated with IS independent of the traditional cardiovascular risk factors in co-dominant and dominant models (P=0.003, q=0.027; P=0.00006, q=0.0108; respectively). Moreover, the combination of rs1049255 CC+CT and rs841 GA+AA genotypes was associated with significantly higher risk for IS after adjustments (OR=1.73, 95% CI: 1.27–2.35, P<0.0001, q<0.0001).

Conclusion:

The data suggest that genetic variants within the NO-forming pathway alter susceptibility to IS in Chinese Han population. Replication of the present results in other independent cohorts is warranted.     

CYP4F2、CYP2C9和VKORC1基因多态性对中国汉族非瓣膜性房颤患者使用华法林剂量的影响

目的：探讨CYP4F2等基因多态性及临床特征对中国汉族非瓣膜性房颤患者华法林剂量的影响。方法：采用连接酶检测反应（LDR）检测CYP2C9＊3、VKORC11173和CYP4F2的基因型。多元线性回归分析CYP4F2等基因多态性及临床特征对中国汉族非瓣膜性房颤患者华法林剂量个体差异的影响。结果：CYP4F2TT患者的华法林剂量显著高于野生型患者（[3.04±0.98）mgvs.（2.60±0.84）mg,P=0.034）];CYP2C9＊3、VKORC11173和CYP4F2的基因多态性、年龄、体重、血栓史、联合应用胺碘酮以及β受体阻滞药解释了51.7%的华法林剂量个体差异,其中CYP4F2的基因多态性的贡献率为4.8%。结论：CYP4F2的基因多态性对中国汉族非瓣膜性房颤患者的华法林剂量有显著影响;基于临床特征与基因多态性的个体化给药方案可能有助于进一步提高非瓣膜性房颤患者的抗凝安全性。     

哌拉西林钠-他唑巴坦钠优选给药方案的评估及应用的研究现状

目的为哌拉西林钠-他唑巴坦钠的临床合理用药提供参考。方法对哌拉西林钠-他唑巴坦钠的优选给药方案的药动/药效学研究、临床试验及具体实施情况进行综述。结果哌拉西林钠-他唑巴坦钠的优选给药方案（延长输注或持续输注）可最大化地达到药效学目标,改善临床有效性。结论需积极完善优化方案用于临床实践的策略。     

Pharmacokinetics of tralokinumab in adolescents with asthma: implications for future dosing

AimsTralokinumab, an investigational human immunoglobulin G4 monoclonal antibody, potently and specifically neutralizes interleukin‐13, a central mediator of asthma. Tralokinumab has shown improvements in clinical endpoints in adults with uncontrolled asthma. The present study explored the pharmacokinetics (PK) and safety of a single tralokinumab dose, and utilized a population PK modelling and simulation approach to evaluate the optimal dosing strategy for adolescents.MethodsAdolescent subjects with asthma, using daily controller medication, received a single subcutaneous dose of tralokinumab 300 mg. Safety, immunogenicity and PK data were collected during a 57‐day follow‐up. A population PK model was developed using data from the present study and prior studies in adults. Simulations were performed to evaluate dose adjustment requirements for adolescents.ResultsTwenty adolescents (12–17 years) were enrolled; all completed the study. No clinically relevant safety findings or antidrug antibodies were detected. PK parameters were similar to those observed in adults. PK modelling showed that body weight was a minor predictor of tralokinumab PK; after incorporating body weight into the PK model, a 15% (nonparametric 95% confidence interval 5%, 26%) lower clearance was found in adolescents compared with adults [173 (151, 209) vs. 204 (191, 229) ml day^–1]. Simulations showed no therapeutically relevant differences in exposures between adolescent and adult populations, and similar PK profiles for weight‐based (4 mg kg^–1) and fixed (300 mg) fortnightly subcutaneous doses of tralokinumab.ConclusionSingle‐dose administration of tralokinumab 300 mg in adolescents was well tolerated, with a PK profile similar to that in adults. Exposure predictions suggest that dose adjustment is not required for adolescents.