头孢氨苄体内药代动力学实验

头孢氨苄为第一代头孢菌素,主要用于敏感菌引起的尿路、呼吸道及皮肤软组织等轻症感染。由于其口服吸收迅速而完全,耐     

单克隆抗体药物的药代动力学研究进展

单克隆抗体药物在近30年时间里经历了快速的发展。由于极大的理化和生物学特征差异,单克隆抗体和传统小分子药物在药代动力学的特征和形成机制上具有非常大的不同。充分了解这些机制和特征可以有效地指导单克隆抗体药物的筛选和开发,并支持其安全性的评估和临床给药方案的设计。该文的目的就是从吸收、分布和消除等几个方面对单克隆抗体药物的药代动力学的特征和机制,以及其人体药代动力学的预测进行综合的归纳和阐述。     

基于MATLAB的药代动力学实验数据处理及参数估计

介绍了MATLAB在药代动力学中实验数据处理的基本方法并对利用MATLAB进行双指数模型拟合与常用EXCEL软件进行双指数模型拟合以及参数求解的方便性、准确性作出了评价。     

头孢唑肟的药代动力学

头孢唑肟(Ceftizoxime,CZX)是由日本藤泽药品研究所开发的新型第三代头孢菌素。自1978年以来,国外进行的大量动物及人体实验,临床验证结果表明,该药具有强大的体外抗菌活性、广泛的抗菌谱、对β-内酰胺酶高度稳定、机体对之有良好的耐受性、有较好的体内药代动力学特征、以及显著的临床疗效等特点。本文对头孢唑肟的构效关系、药代动力学特点及给药方案的探讨进行综述。     

性别对药代动力学的影响

性别对药代动力学的影响越来越受到重视,药代动力学的性别差异是药物作用个体差异的主要因素。了解药代动力学的性别差异有利于提高用药的安全性和有效性。近年来关于药代动力学性别差异的研究取得了较大的进展,本文综述了相关领域的研究结果。     

基于辛伐他汀对厄贝沙坦药代动力学影响的实验探索

目的对基于辛伐他汀对厄贝沙坦药代动力学影响进行分析和探讨。方法此次临床研究主要以24只白兔为实验对象,采用随机分配的原则,将所有白兔分成对4组,每个组别各6例。分别为诱导3 d组、诱导5 d组、对照3 d组以及对照组5 d组。对照组实施浓度为2%的羧甲基纤维素以及厄贝沙坦灌胃,实验组实施辛伐他汀的2%羧甲基纤维素溶液合并厄贝沙坦灌胃。使用HPLC-荧光法对白兔的血药浓度进行检测。结果经临床研究结果显示,对照组5 d与诱导5 d组的药代动力学参数差异存在统计学意义,P<0.05。诱导3 d组以及诱导5 d组药代动力学参数差异存在统计学意义,P<0.05。结论经临床研究结果表明,诱导5 d组对厄贝沙坦的药代动力学存在显著的影响,影响机制可能与P-gp密切相关。     

Dirithromycin的药代动力学

Dirithromycin为新大环内酯类抗生素.用于口服的片剂为肠衣片,每片含Dir-ithromycin250mg.本品每日1次服用500mg可用于治疗各种呼吸道和皮下软组织感染.Dirithromycin和其具有抗菌活性的代谢产物红霉环胺(Erythromycyclamine)的抗菌谱和作用方式与红霉素相同.本文报告Dirithromycin的药代动力学.     

头孢哌酮的临床药代动力学

头孢(口派)酮是结构上接近于头孢孟多、哌拉西林的半合成哌嗪头孢茵素.它对需氧、厌氧的革兰阳性及包括绿脓杆菌在内的革兰阴性菌均有很广泛的作用谱(表1),在最近几年已有不少关于它的药代动力学著述发表.     

AZTREONAM的药代动力学研究

6名健康志愿者分次接受肌注、静注和静滴Aztreonam 1g后,平均高峰血浓度分别为44.6、134.4和111.3μg/ml。三者的消除半衰期在1.8～1.9小时之间。肌注后吸收迅速完全,生物利用度约90％。24小时内尿排出率为给药量的70％。根据Aztreonam的药代动力学和抗菌活性,提出了治疗不同感染的给药方案。     

Plasma kinetics and urinary elimination of saccharin in man

The plasma kinetics and urinary elimination of saccharin were studied in 3 groups each of 5 healthy male volunteers given the sweetener as three different single oral doses (50, 150 and 333 $\text{mg}\text{60 kg}$ body weight). Saccharin concentrations were determined by gas liquid chromatography-stable isotope dilution mass fragmentography.The compound was rapidly absorbed through the gastrointestinal tract, reaching plasma peak concentrations between 30 and 60 min after intake. Plasma saccharin elimination was also fast, with a monoexponential pattern of decay. At the 3 doses studied saccharin was excreted in urine within a few hours, about 60% of the dose being excreted unchanged at 6 h and 76% at 24 h.     

Kinetics of monosodium glutamate in relation to its neurotoxicity

Glutamic acid (GA) plasma levels were measured after oral administration of monosodium glutamate (MSG) to laboratory animals, in relation to several variables. Adult mice and rats show similar GA peak plasma levels, area under the curve (AUC) and apparent half-life (T ), while in guinea pigs the values for all these kinetic parameters are higher. Newborn rats and, to a lesser extent, newborn mice show a larger AUC and T than the adults, while the opposite was observed in guinea pigs. Within a given animal species the peak level and AUC, but not the T , increase with the dose of MSG and with the concentration at which the dose is administered.In human volunteers oral administration of MSG (60 ) results in higher plasma peak levels and AUC when MSG is given at 8% as compared to 2% solution.Mouse brain and guinea pig brain GA levels are not affected by oral MSG until the GA plasma level exceeds the basal plasma concentrations by a factor of about 20.These data are utilized to discuss the relevance for man of the neurotoxic effects induced in rodents by MSG.     

Estimation of AUC or Partial AUC Under Test-Result-Dependent Sampling

The area under the receiver operating characteristic (ROC) curve (AUC) and partial area under the ROC curve (pAUC) are summary measures used to assess the accuracy of a biomarker in discriminating true disease status. The standard sampling approach used in biomarker validation studies is often inefficient and costly, especially when ascertaining the true disease status is costly and invasive. To improve efficiency and reduce the cost of biomarker validation studies, we consider a test-result-dependent sampling (TDS) scheme, in which subject selection for determining the disease state is dependent on the result of a biomarker assay. We first estimate the test-result distribution using data arising from the TDS design. With the estimated empirical test-result distribution, we propose consistent nonparametric estimators for AUC and pAUC and establish the asymptotic properties of the proposed estimators. Simulation studies show that the proposed estimators have good finite sample properties and that the TDS design yields more efficient AUC and pAUC estimates than a simple random sampling design. A data example based on an ongoing cancer clinical trial is provided to illustrate the TDS design and the proposed estimators. This work can find broad applications in the design and analysis of biomarker validation studies.     

Comparative evaluation of oral systemic exposure of 56 xenobiotics in rat,dog, monkey and human

The prediction of human pharmacokinetics is often based on in vivo preclinical pharmacokinetic data. However, to date, no clear guidance has been available about the relative ability of the major preclinical species to estimate human oral exposure. The study was conducted to survey the literature on oral pharmacokinetic parameters in rat, dog, monkey and human, and to compare various methods for prediction of oral exposure in humans. Fifty–six non–peptide xenobiotics were identified with oral pharmacokinetic data in rat, dog, monkey and human, and comparison of the data from each species to humans was conducted along with an evaluation of the molecular features of these compounds. Monkey liver blood flow–based oral exposure was qualitatively and quantitatively more predictive of human oral exposure than rat or dog. Furthermore, generation of data in three versus two preclinical species did not always improve human predictivity. The use of molecular properties did not substantially improve the prediction of human oral exposure compared with the prediction from monkey alone. These observations confirm the continued importance of non–human primates in preclinical pharmacokinetics, and also have implications for pharmacokinetic lead optimization and for prediction of human pharmacokinetic parameters from in vivo preclinical data.     

Impact of sampling time deviations on the prediction of the area under the curve using regression limited sampling strategies

The regression limited sampling strategy approach (R‐LSS), which is based on a small number of blood samples drawn at selected time points, has been used as an alternative method for the estimation of the area under the concentration–time curve (AUC). However, deviations from planned sampling times may affect the performance of R‐LSS, influencing related therapeutic decisions and outcomes. The aim of this study was to investigate the impact of different sampling time deviation (STD) scenarios on the estimation of AUC by the R‐LSS using a simulation approach. Three types of scenarios were considered going from the simplest case of fixed deviations, to random deviations and then to a more realistic case where deviations of mixed nature can occur. In addition, the sensitivity of the R‐LSS to STD in each involved sampling point was evaluated. A significant impact of STD on the performance of R‐LSS was demonstrated. The tolerance of R‐LSS to STD was found to depend not only on the number of sampling points but more importantly on the duration of the sampling process. Sensitivity analysis showed that sampling points at which rapid concentration changes occur were relatively more critical for AUC prediction by R‐LSS. As a practical approach, nomograms were proposed, where the expected predictive performance of R‐LSS was provided as a function of STD information. The investigation of STD impact on the predictive performance of R‐LSS is a critical element and should be routinely performed to guide R‐LSS selection and use. Copyright © 2015 John Wiley & Sons, Ltd.     

A Review of: “Clinical Trials: A Methodologic Perspective”, Second Edition,by S. Piantadosi

It is well known that outliers can have a significant effect on the conclusion of a bioavailability/bioequivalence study. Existing approaches for outlier detection are ANOVA type based on the assumptions on log-AUC, and they are disconnected from the pharmacokinetics (PK) literature. However, the observations from a bioavailability/bioequivalence study are the correlated concentrations, not the AUCs. Thus, the estimate of AUC and the related variance estimate may not be accurate because of the exclusion of the correlation nature. In this paper, based on the predicted concentrations from a functional linear model which takes into consideration of the correlation structure of concentrations, a residual analysis is proposed to detect the outliers. With this approach, the distributional assumption is on the observed raw concentration instead of the summarized parameter AUC, and this approach takes the repeated measurements nature of the concentration curve into consideration, which is in line with population PK concept and could result in a more accurate variance estimate. A real data set is used to demonstrate the proposed approach.     

Optimal threshold selection methods under tree or umbrella ordering

Receiver operating characteristic (ROC) curve is a popular tool for evaluating diagnostic accuracy of biomarkers. In ROC framework, there exist several optimal threshold selection methods for binary classification. For diseases with multi-classes, an important category of scenarios is tree or umbrella ordering in which the marker measurement for one particular class is lower or higher than those for the rest classes. Tree or umbrella ordering has important clinical applications, especially in the molecular diagnostics of cancer subtypes. The ROC curve has been extended to a typical ROC framework for tree or umbrella ordering (denoted as TROC). In this paper, we investigate several methods for optimal threshold selection under tree or umbrella ordering. Simulation studies are carried out to explore the performance of these threshold selection methods. A real microarray data set on lung cancer is analyzed using the proposed methods.     

有限取样法估算中国肾移植患者单个核细胞内 他克莫司的暴露量

目的:建立预测肾移植患者服用他克莫司后外周血单个核细胞(PBMC)内暴露量的有限取样法(LSS)模型.方法:23例接受包括他克莫司在内的三联免疫疗法的肾移植患者,收集给药后0、0.5、1、1.5、2、4、6、8、10、12 h全血标本提取PBMC,采用LC-MS/MS法测定PBMC中他克莫司浓度.以多元线性分析法,获得他克莫司AUC0～12h的LSS估算模型.用Bland-Altman评价模型的预测值和实际测量值的一致性.结果:建立了包含1～4个采样时间点的LSS模型(r2=0.570～0.989).预测他克莫司AUC0～12h的最佳模型为C2-C4-C6-C10(r2=0.989).C0.5-C6模型(r2=0.849)则适用于短期需要监测的门诊患者.结论:由2-4个时间点组成的LSS模型是评估中国肾移植患者他克莫司AUC0～12 h的有效方法,可为临床监测他克莫司细胞内暴露量提供参考.     

Monosodium glutamate kinetic studies in human volunteers

(a) A kinetic study of plasma glutamic acid (GA) was made after mono-sodium glutamate (MSG) administration to human volunteers. MSG was given at doses of 30,60 and 120 mg/kg in a bouillon and of 60 mg/kg in tomato juice. In another experiment a normal meal was consumed without added MSG. (2) Plasma area under the curve (AUC) was found to be lower in females than in males. (3) Plasma AUC was lower when MSG was taken in tomato juice than when consumed in bouillon. (4) Consumption of the normal meal did not result in any significant increase in plasma GA.     

Kinetics of 3-tert-butyl-4-hydroxyanisole (BHA) in man

High-resolution capillary gas chromatography-mass spectrometry with selective ion monitoring and using deuterated 3-tert-butyl-4-hydroxyanisole (BHA) as an internal standard was used to measure BHA in the plasma and urine of human volunteers after oral administration of 30 or 5 mg of the compound in olive oil. Pharmacokinetic studies showed similar plasma-concentration profiles in subjects treated with either level of BHA. About 20% of the administered dose was excreted as BHA glucuronide in the urine within the first 24 hr.