���������ù�ص�Ⱥ��ҩ��ѧ�о�

??OBJECTIVE To investigate the population pharmacokinetics of vancomycin (VAN) in Chinese neonates by nonlinear mixes-effects modeling software (NONMEM). METHODS One hundred and fifty-four VAN serum trough data from 91 neonatal patients were retrospectively collected from Suzhou Hospital Affiliated to Nanjing Medical University. A one-compartment model with first order elimination was used to describe structure pharmacokinetic model, and physiological maturity model was employed to screen covariates. The stability and prediction of the final model were evaluated by Bootstrap and normalized prediction distribution error (NPDE). The final model was applied to evaluate the percentage of AUC_{0-24 h}/MIC ?? 400 in neonatal patients by Monte Carlo Simulation, who were stratified according to gestational weeks, age and serum creatinine. RESULTS The weight, postmenstrual age and serum creatinine were identified as the most significant covariate on clearance. Bootstrap and NPDE showed the satisfactory stability and prediction performance of the final model. Moreover, the final model indicated that 96% of neonates with low serum creatinine (15 ??mol??L^-1) were not getting AUC_{0-24 h}/MIC??400, according to the current guidelines. CONCLUSION The population pharmacokinetic model of vancomycin in neonates is established successfully and could provide basis for the individualized therapy in neonatal patients.     

老年患者替考拉宁群体药动学模型的建立及临床应用

目的 本研究应用非线性混合效应法(NONMEM)建立中国老年患者替考拉宁PPK模型.方法 收集102名老年患者共150个替考拉宁的血药浓度,采用一室模型建立替考拉宁的基础模型,分别考察SEX、AGE、WT、SCr、BUN、CCr等协变量对固定效应参数V、CL的影响,建立群体药动学最终模型.对最终模型拟合优度及稳定性进行...     

替考拉宁在中国成人患者中的群体药动学研究

目的建立中国成年患者的替考拉宁(teicoplanin,TEC)群体药动学(population pharmacokinetics,PPK)模型,考察TEC药动学参数的影响因素。方法前瞻性收集139例革兰阳性球菌感染患者静脉注射TEC后的222份常规监测血药浓度和相关信息,采用一级消除的一室模型进行数据拟合,并应用非线性混合效应模型(nonlinear mixed effect model,NONMEM)程序建立PPK模型。采用Bootstrap、正态预测分布误差法(normalized predictive distribution error,NPDE)进行最终模型评价。利用蒙特卡洛模拟法对给药方案进行优化。结果确定了肌酐清除率(creatinine clearance,CLcr)、白蛋白(albumin,ALB)为影响TEC清除率的主要因素。最终模型为:CL(L·h^-1)=1.24×(CLcr/77)0.564×31/ALB;V(L)=69.2。验证表明,模型稳定、有效,且有较好的预测效能。对于不同ALB和CLcr的多数患者起始负荷剂量400 mg/q12h,iv,3次,维持剂量400~800 mg·d^-1的给药方案可达有效治疗谷浓度。严重感染者需调整负荷剂量至800 mg/q12h,iv,3次,维持剂量400~800 mg·d^-1的给药方案来确保血药浓度达到15 mg·L^-1以上。结论本实验报道了CLcr、ALB对TEC清除率有显著影响,所建模型对TEC在中国成人患者中实现个体化给药具有重要应用价值。     

���ƻ������ù��Ⱥ��ҩ��ѧ��ģ����֤��ȷ��

??OBJECTIVE To choose a PPK model of vancomycin most suitable for Chinese pediatric patients, in order to guide the dosage adjustment.METHODS Based on the database of PubMed and CNKI, all studies regarding vancomycin population pharmacokinetics were investigated and their basic information including PPK models was extracted. The data of Chinese pediatric patients who were administered vancomycin and received therapeutic drug monitoring(TDM) were introduced into the reported final PPK models, and the fitting was conducted by model fitting graphics. RESULTS Twelve vancomycin PPK studies during 1986-2014 were included. As judged by the correlation coefficient (R) and R-square(R2) between predicted concentration and measured concentration, the models 4 and 9 presented a relatively better fitting with the data of Chinese pediatric patients we collected. The VPC fitting demonstrated that number 1 model achieved the best fitting. However, because the limited data used in this study was based on irregular sampling time, so the VPC test results were difficult to be distinguished and could only be used as a secondary reference. On the other hand, NPDE has corresponding statistical test, and its evaluation ability for the model is not affected by the factors of the experimental design. NPDE analysis showed that one-compartment model was better than two-compartment model, and model 4 and model 9 achieved better fitting to the collected data than others.CONCLUSION The fitting effects of most reported vancomycin PPK models, except individual models, were poor for the TDM data of Chinese pediatric patients, therefore it is necessary to establish a vancomycin population pharmacokinetic model particularlly for Chinese pediatric patients, in order to guide dosage adjustment more accurately.     

Ⱥ��ҩ��ѧ�ڳ��˸���ֲ��ڷ�����Ī˾�е��о���չ

??Tacrolimus is widely used as a first-line immunosuppressant after adult liver transplantation. However, because of narrow treatment window and pharmacokinetic individual differences, it is difficult to formulate individualized dosing regimens in short term. Pharmacokinetic parameters that estimated by population pharmacokinetics(PPK) can provide a preliminary individualized regimen for early postoperative patients. This paper collected literatures on PPK modeling of orally administered tacrolimus in adult liver transplantation patients through literature search. And multiple influencing factors of PPK model was mainly summarized, such as demographic characteristics, blood biochemical index, combined medication, liver and kidney function, genetic factors, postoperative time and dosage. It will provide literature support for the development of individualized dosing regimens for oral tacrolimus recipients using the PPK protocol for adult liver transplantation.     

肿瘤病人静脉输注甲氨蝶呤的群体药动学研究

 目的建立甲氨蝶呤(MTX)在肿瘤病人静脉输注的群体药动学(PPK)模型,并考察模型的预测能力。方法收集61名接受MTX静脉输注的肿瘤病人的血清MTX浓度276个,利用PPK软件PKBugs,定量分析体重(WT)、身高(HT)、年龄(Age)、体表面积(BSA)、血清肌酐浓度(Scr)和肌酐清除率(CLcr)对PK参数的影响,并计算清除率(CL)、室间清除率(Q)、中央分布容积(V₁)和外周分布容积(V₂)。采用浓度预测误差为指标,评估PPK模型对验证组26名病人45个血清MTX浓度预测的准确性和精密度。结果MTX在肿瘤病人静脉输注的体内过程符合1级消除2室开放模型。PPK模型为:LnCL=1.98+0.0096×(WT-67.8)-0.72×(Scr-1.04),LnQ=-1.39,LnV₁=3.41,LnV₂= 1.93-0.013×(Age-42.4)。CL,Q,V₁和V₂及其个体间变异系数分别为(7.84±2.42)L·h^-1(37%),(0.36±0.40) L·h^-1(129%)、(31.46±11.03)L(51%)和(10.53±12.53)L(115%)。模型预测偏差为0.097 mg·L^-1,精密度为0.23 mg·L^-1,相对误差为136%;预测浓度与观察浓度的配对t检验P值为0.10,无显著差异。结论此PPK模型能够较准确地描述MTX在肿瘤病人静脉输注的PPK特征,其预测能力尚待进一步评估。     

Effect of naringenin in Qianggu capsule on population pharmacokinetics in Chinese women with primary osteoporosis

OBJECTIVE:To characterize naringenin(NAR) population pharmacokinetics(PPK) in Chinese women with primary osteoporosis.METHODS:Ninety-eight female patients with primary osteoporosis from the Jingshan,Beixinqiao,Jiaodaokou,Chaoyangmen,and Donghuamen communities in Beijing,China,aged 40 to 80 years,received oral Qianggu capsules(250 mg).Blood samples were collected before and at 0.5,1,2,3,4,6,8,10,12,and 24 h after administration.The concentration of NAR in the blood samples was measured using high performance liquid chromatography-tandem mass spectrometry.PPK analyses were performed with nonlinear mixed-effect modeling software(version 7.1.2,PsN3.2.12).The clearance(C1),central distribution volume(V),absorption rate constant(Ka1),peripheral distribution volume(VII),and inter-compartmental clearance(CLII) were set as parameters and estimated by the base model,covariate model,and final model.Kidney-Yang deficiency[Shenyangxu(SYAX)]and liver-kidney-Yin deficiency(Ganshenyinxu) are patterns of symptoms in Traditional Chinese Medicine that were set as covariates,along with age,height,blood urea nitrogen,serum creatinine,alanine transaminase,aspartate transaminase,and hyperlipidemia.Both stepwise forward and backward procedures were accomplished to build models.The final model was evaluated by internal and external validation,visual predictive check,bootstrap,and leverage analysis.RESULTS:A one compartment open model with first order degradation was the best fitted to the concentration-time profiles following oral administration of NAR.The mean of population parameters of the final model,C1,SYAX on C1,V,Ka1,CLII,and VII,were measured to be 37.6 L/h,0.427 L,123 L/h,0.12/h,0.3056,and 1.446,respectively.Inter-individual variability was estimated and SYAX was identified as a significant covariate.CONCLUSION:The population pharmacokinetic model described in this study could effectively characterize the pharmacokinetic profile of NAR following administration of a single dose of oral Qianggu capsules in Chinese women with primary osteoporosis.Among the tested covariates,only SYAX was a significant factor.     

�������ڷν�˲������е�Ⱥ��ҩ�ﶯ��ѧ�о�

??OBJECTIVE To characterize the population pharmacokinetics of isoniazid in Chinese tuberculosis patients. METHODS A total of 321 serum samples were obtained from 201 patients receiving oral doses of isoniazid. The effects of 16 covariates including demographics and blood tests to isoniazid??s pharmacokinetics were evaluated. Data analysis was performed using non-linear mixed effects modeling (NONMEM). Prediction-corrected visual prediction check was performed for model evaluation. RESULTS A two-compartment model with first-order absorption and linear elimination can well fit the isoniazid concentration-time data. A ??MIXTURE?? model was used to separate the subpopulation of ??subgroup A?? and ??subgroup B??. Typical clearance of the two subpopulations were 82.7 and 19.3 L??h^-1, respectively. CONCLUSION Model validation shows the final model is reliable, which could be used for individualized treatment.     

ҩ������ѧ/ҩЧ����ѧģ�ͽ�����ؿ���ģ���Ż���ͯ�ͼ������ֽ��ɫ���������Ⱦ�����ù�ظ�ҩ����

??OBJECTIVE To optimize vancomycin regimen in children with MRSA infection. METHODS Vancomycin AUC_0-24/MIC predictions were performed across a range of dosages (20-70 mg??kg^-1??d^-1) using a Monte Carlo simulation (n=10 000). AUC_0-24 was calculated as daily dose divided by vancomycin clearance, and daily dose was fixed for a given simulation. The MIC distribution for MRSA was obtained from the RESULTS of clinical laboratory, the First Affiliated Hospital of Guangxi Medical University, from 2012 to 2014 (n=430;30%??0.5 mg??L^-1; 58.6%= 12 mg??L^-1; and 11.2%=2 mg??L^-1; 0.2%=4 mg??L^-1). RESULTS With increasing vancomycin daily dose, the percentage of patients predicted to achieve AUC_0-24/MIC >400 similarly increased. At 35 mg??kg^-1??d^-1, the percentage predicted to achieve AUC_0-24/MIC >400 was 99.41% when MIC was 0.5 mg??L^-1. However, the dosage rose to 65 mg??kg^-1??d^-1 when MIC was 1 mg??L^-1. At this regimen, the percentage predicted to achieve AUC_0-24/MIC >400 was 97.55%. At a MIC of 2 mg??L^-1 and more, none of the dosages predicted to achieve AUC_0-24/MIC>400. CONCLUSION Recommended empiric vancomycin dosing in children should be above 35 mg??kg^-1??d^-1 when MIC is 0.5 mg??L^-1. At the MIC is 1 mg??L^-1, the recommended regimen should be over 65 mg??kg^-1??d^-1.     

用NONMEM法建立中国癫痫儿童丙戊酸钠的群体药动学模型

 目的建立中国癫痫儿童丙戊酸钠(VPA)的群体药动学(PPK)模型,促进个体化用药。方法回顾性地收集246例癫痫患儿应用VPA的临床数据,血药浓度都是常规监测的稳态浓度。将患儿分为两组,PPK模型组(n=146):用NONMEM软件求算PPK参数值,建立基本模型和最终模型;PPK验证组(n=100):分别用基本模型和最终模型预测PPK验证组患儿的血药浓度,比较两模型的平均预测误差(MPE)、预测误差均方(MSPE)、平均预测误差平方根(RMSPE)和权重残差(WRES),进行模型验证。结果用NONMEM法拟合为一室一级吸收模型,PPK基本模型的参数为:K_a 2.38 h^-1,Vd 6.54 L,CL 0.232 L·h^-1;最终模型参数为:Ka 2.38 h^-1,V_d(2.03+0.189).体重(L),CL(0.097 8+0.010 4).年龄(L·h^-1)。基本模型经PPK验证组检验的结果,MPE,MSPE,RMSPE,WRES及其95% CI分别为:-25.03(-32.74,-17.32),4 105.71(2 803.93,5 407.49),44.34(38.29,50.39),-0.03(-0.11,0.05);最终模型经PPK验证组检验的结果,MSE,MSPE,RMSPE,WRES及其95% CI分别为:-1.29(-6,3.4),1 268.38(1 050.64,1 486.12),28.46(25.66,31.26),0.12(-0.04,0.28)。最终模型比基本模型更优化、预测更准确。结论用NONMEM软件成功地建立了中国癫痫儿童VPA的PPK模型。