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。     

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??OBJECTIVE To establish a population pharmacokinetics(PPK) model of vancomycin in adult patients and investigate the factors influencing vancomycin clearance.METHODS The nonlinear mixed-effect model(NONMEM) was used to investigate the population characteristics of vancomycin in adult patients and the serum cystatin C was used as a marker of renal function. The final model was built by forward inclusion approach and backward elimination method. Fitting effect of the model was evaluated by the goodness of fit plots(GOFs). Nonparametric Bootstraps and normalized prediction distribution errors(NPDE) were performed to evaluate the robustness and predictive efficacy of the final model. External model evaluation was conducted using an independent dataset to evaluate the model predictability. RESULTS Vancomycin PPK model was set up via 147 serum trough concentration data from 95 adult patients. The estimated population typical values of clearance rate and apparent volume of distribution were 3.57 L??h^-1 and 63.30 L, respectively. The main factor influencing clearance was renal function. The GOFs showed that the final model was stable and effective, and the fitting degree of the final model was better than that of the base model. The robust rate verified by Bootstrap was 99.45%. All of the relative biases between the median of parameters validated by Bootstrap and the estimated parameters of final model were within ??3%, and the 95% confidence intervals of these validated parameters did not include zero. The NPDE followed the N(0,1) distribution with a global adjust P value of 0.334, which indicated that the model had a high predictive accuracy. External evaluation was performed via an independent dataset of 40 concentration data from 20 patients. The mean prediction error(MPE) and mean absolute prediction error(MAPE) based on population predictions(PRED) was -1.90% and 24.34%, respectively. CONCLUSION Vancomycin PPK model established in the study is of as a good stability and high predictive accuracy, as a reference for developing individualized administration regimens.     

中药上市后人体群体药代动力学试验设计要点

中药人体群体药代动力学(population pharmacokinetics,PPK)是定量考察患者群体中药物浓度决定因素的一门学科.进行合理的中药PPK试验设计可为临床用药提供真实客观的数据,进而促进临床个体化用药方案的制订.该文参考历年文献,并结合实际工作经验,针对中药人体PPK试验设计的要点进行总结,主要包括研究对象的选择、指标的选取、样本采集方案设计、血液样本分析方案设计、数据分析方案设计.     

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??OBJECTIVE The analyze the results of tacrolimus blood concentrations in patients with myasthenia gravis and the influencing factors, provide references for rational clinical application. METHODS The data of tacrolimus blood concentrations and medical records in patients with myasthenia gravis in hospital were collected and analyzed from January 2013 to December 2015.Tacrolimus whole-blood concentrations were measured by chemiluminescent microparticle immunoassay and CYP3A5^*3 gene polymorphism were detected by digital fluorescence molecule hybridization fluorescence. RESULTS The range of tacrolimus trough concentrations were from 0 to 64.71 ng??mL^-1 and the average of concentration was(5.22??5.80) ng??mL^-1 in 254 cases with 171 myasthenia gravis patients. The results showed that there was a certain correlation between concentration and dosage, and concentration was also related other factors such as the combination of drugs and CYP3A5^*3 gene polymorphism. CONCLUSION The concentration of tacrolimus are affected by many factors, so when tacrolimus is used, multiple factors should be considered comprehensively to achieve individualized treatment.     

ELISA法监测肾移植患者他克莫司全血浓度448例次

 目的 通过监测肾移植后患者他克莫司全血浓度,观察并建立他克莫司在三联免疫抑制用药方案中的理想治疗窗,为临床合理应用提供参考。方法 用ELISA法测定他克莫司全血浓度,对75例患者的448例次监测结果进行比较分析。结果他克莫司全血浓度随移植后时间延长而逐渐下降。肾移植后1个月内、第2～3个月、第4～6个月和>6个月时,用ELISA法监测他克莫司全血谷浓度的治疗窗范围应分别为,8～15,6～12,5～10和3～8μg·L^-1,较为适宜。结论 常规监测他克莫司全血浓度,按推荐治疗窗调整给药方案,可获得满意的免疫抑制治疗效果。     

CYP3A5和MDR1基因多态性与肝移植病人他克莫司浓度/剂量比的关系

 目的研究肝移植术后患者的细胞色素P4503A5酶(CYP3A5)和多药耐药蛋白(MDR1)基因多态性对他克莫司浓度/剂量比的影响。方法记录患者的体重、他克莫司剂量和血药浓度等指标,采用聚合酶链式反应-限制性内切片段长度多态性(PCR-RFLP)方法对肝移植患者进行基因分型,比较不同基因型患者之间他克莫司的浓度/剂量比。结果CYP3A5*1/*1和*1/*3型患者的他克莫司浓度/剂量比明显低于*3/*3型患者(P<0.01),MDR1的3435和2677位点各基因型分组之间无明显差异(P>0.05)。结论CYP3A5基因*3多态性与他克莫司血药浓度/剂量比具有显著相关性,*1/*1和*1/*3型的患者拟取得相似的血药浓度要比*3/*3型患者服用更高剂量的他克莫司,用药前检测基因型可以更有效地对他克莫司进行剂量调整。     

酶联免疫法与微粒子酶免疫法检测全血他克莫司浓度的比较

 目的：比较微粒子酶免疫法（MEIA）和酶联免疫法（ELISA）检测全血他克莫司浓度的特点，总结其在临床他克莫司全血浓度检测中的应用。方法：分别以MEIA和ELISA平行测定高、中、低标准浓度的他克莫司血样，比较两种方法的准确度、精密度、相关性及各自特点。以他克莫司谷浓度测定结果结合器官移植受者的临床情况，比较MEIA法和ELISA法在心脏、肝脏、小肠和肾脏移植患者全血他克莫司谷浓度治疗窗的范围。结果：MEIA和ELISA方法学的回收率分别为(96.4±1.4)%和(104.7±1.8)%，RSD分别为(7.7±2.0)%和(8.2±1.7)%，r=0.96。与MEIA法相比，ELISA法灵敏度更高、测试成本更低，但分析速度较慢。MEIA和ELISA可采用相同的谷浓度治疗窗范围。结论：两种方法均准确可靠，适用于临床他克莫司的治疗药物监测。     

羟基喜树碱注射液在肿瘤患者体内的群体药代动力学

 目的 研究羟基喜树碱在肿瘤患者的群体药动学（ PPK ）特征,为临床调整肿瘤患者的个体用药提供新途径。 方法 60 例肿瘤患者静脉滴注羟基喜树碱后,采集不同时间的静脉血样 260 个点, HPLC 测定羟基喜树碱的血药浓度。以非线性混合效应模型（ NONMEM ）程序法分析羟基喜树碱群体药代动力学参数。 结果 羟基喜树碱二室模型最终的群体药动学参数群体标准值 <> CL ₁ , <> V ₁ , <> CL ₂ , <> V ₂ 分别为（ 18.3 ± 4.71 ） L·h-1 ,（ 12.6 ± 2.15 ） L ,（ 18.3 ± 2.32 ） L·h-1 ,（ 26.8 ± 4.81 ） L 。男性的中央室清除率是女性的 1.512 倍,群体模型有较好的拟合优度。 结论 NONMEM 法对二室模型群体参数估算的血药浓度值与实测值有良好的相关性,性别对中央室清除率参数影响较大。本试验获得的羟基喜树碱群体参数可以为羟基喜树碱在肿瘤病人的临床个体化用药提供支持。     

供体CYP3A5基因多态性影响肝移植术后FK506的个体化用药

 目的探讨肝移植术后口服免疫抑制剂FK506的剂量及其全血谷浓度的个体差异与供体的肝药酶P450 3A5(CYP3A5)基因多态性的关系。方法观察44例接受肝移植的受体在术后1,2周及1月的FK506服药剂量和全血药物谷浓度,并利用PCR-限制性片断长度多态性(PCR-RFLP)方法和DNA直接测序法检测对应供体CYP3A5基因内含子3第6 986位A/G单核苷酸多态性(CYP3A5*3),分析基因多态性与FK506服用剂量及全血谷浓度/剂量比值(C/D)的相关性。结果肝移植术后FK506的口服需药量在个体间存在极大差异,在术后2周及1月,CYP3A5*3/*3基因型患者需要的剂量最小,分别为(0.074±0.042)和(0.084±0.045)mg·kg^-1·d^-1,而C/D比值明显高于*1/*1基因型患者。结论肝移植术后受体FK506服用剂量的个体化差异与供体CYP3A5*1/*3基因多态性密切相关,分析供体CYP3A5*1/*3基因多态性可以为肝移植术后FK506的个体化用药提供可靠的参考指标。     

西柚汁增加肝移植术患者他克莫司血药浓度的临床评价

 目的评价西柚汁对肝移植患者口服他克莫司谷浓度的影响,探讨西柚汁在肝移植术后抗排异治疗中提高患者他克莫司血药浓度的临床意义。方法对北京大学人民医院肝移植中心的门诊术后患者39例,采用开放、随机、自身对照的方法,干预患者西柚汁和药物服用方法,通过门诊随访收集相应的生理、病理和实验室数据,经统计学分析考察西柚汁对他克莫司稳态血药浓度谷值的影响。同时计算达到相应靶值可能节省的费用。结果在纳入的39例患者中29例为有效病例。西柚汁可明显增加他克莫司稳态谷浓度,平均增加率为(37.1±31.6)%,但并不增加稳态谷浓度的波动性;使血药浓度增加的人群比例为72.4%,平均每人每年可节约的费用约为1.4万元;本试验中疑似西柚汁的不良反应发生率约为10%。结论西柚汁在肝移植术后抗排异治疗中提高大部分患者他克莫司血药浓度有实际的临床意义,但一定要在血药浓度监测条件下,严格遵医嘱进行。