构建沙格列汀PK/PD模型——模拟其在健康人群和肝损伤患者的药动学和药效学

在本次研究中,我们旨在开发和评价沙格列汀的全身生理药代动力学(WB-PBPK)/药效学(PD)模型,模拟其在健康成人及肝功能损害患者中的药代动力学和药效学特性,为特殊患者的临床药学研究提供新方法.基于文献中获取的如logD和血浆蛋白结合率等药物特征参数,建立WB-PBPK模型和PD模型.将模拟所得的血药浓度-时间曲线及...     

药代动力学药效学结合模型的研究进展

临床药代动力学(clinical pharmacokinetics)是研究药物对人体的作用,在体内经时过程及其影响因素[1].因此药代动力学(pharmacokinetics,PK)和药效动力学(pharmacodynemics,PD)研究必需两者结合.为了提高人体药效学研究工作质量,国外正在制定各类药物的替代标志(surrogate marker),作为评价药物治疗后临床症状,体征或实验室检测指标等方面获得治疗成功的的预报.临床药效学研究水平的提高,促进了PK/PD结合模型研究.由于这个领域的日益发展和内容的丰富,显示出PD/PK联合建模的实际应用中的可用性及其生命力,PD/PK联合建模已形成新出现的学科领域和生长点.本文就PD/PK结合模型的基本概念,近年发展,及联系我们在这一领域的研究作简要回顾.     

微透析在药代动力学研究中的应用

微透析是一较新的组织间隙液采样技术，近几年来在体微透析技术在药代动力学和药效学的研究中被广泛应用，本文描述了微透析采样的原理及其在药代动力学中的应用特点，并对其在人体药代动力学研究中的应用进行了介绍。     

药代动力学和药效学结合模型的研究进展

药代动力学-药效学结合模型是将药代动力学和药效学结合起来研究的模型，能描述和预测一定剂量方案下药物的效应-时间过程，还能解释造成这种效应一时间过程的原因。这种结合模型可应用于药物开发的临床前和临床试验的各个阶段。在临床前试验阶段可用于评价药物的体内效价和固有活性、剂型和给药方案的选择及优化等；在临床试验阶段则可用于估算给药剂量一浓度一效应或毒性之间的关系，以及年龄、性另q等对药效的影响等，从而满足新药开发和临床试验的要求。本文综述了近年来的药代动力学一药效学结合模型及其在药物研究开发领域中的应用。     

氯沙坦钾的药理特性和临床应用

氯沙坦钾(Losartan Potassium),全球第一个上市的血管紧张素Ⅱ受体拮抗剂.适用于治疗原发性高血压。人体药代动力学和药效学氯沙坦钾(Losartan Potassium),化学名2-丁基-4氯-1-[[2‘-1(1H-4唑-5-基)[1,1’-联苯基]-4-基]甲基]-1H-咪唑-     

他汀类药物在高脂血症大鼠体内的PK-PD关系研究

目的:探讨他汀类药物在高脂血症大鼠体内暴露水平(药代动力学参数AUC)与药效之间的关系.方法:建立大鼠高脂血症模型,给予不同剂量的他汀类药物干预治疗,进行药代动力学和药效学测定,计算药代动力学/药效学(PK/PD)值,并进行相关分析.结果:TG-AUC在药代动力学(AUC)变化范围内(0～10.96倍)线性关系良好,Y=0.01036X-7.6445(γ=0.9599).胆固醇(CHOL)-AUC、低密度脂蛋白胆固醇(LDL-C)-AUC、高密度脂蛋白胆固醇(HDL-C)-AUC由于中间数据偏低,与预测样本数据偏差太大,线性关系不明显.结论:TG-AUC在药代动力学(AUC)变化范围内(0～10.96倍)线性关系良好,可以在知道药代动力学的相关数据基础上对药效进行预测.     

应用药代动力学／药效学原理指导肺部感染的抗菌治疗

抗菌药物的临床疗效除取决于抗菌谱,抗菌活性外,还取决于它的药代动力学和药效学参数,主要叙述了抗菌药物在呼吸系统的穿透力和同疗效相关的药效学参数。并对肺部感染的治疗方案应当根据药代动力学／药效学原理合理安排进行了讨论。     

手性药物对映体在药效学与药代动力学的相互作用

当手性药物以外消旋体供药用时，其对映体间就可能发生药效学和药代动力学的相互作用。本文综述了手性药物对映体间的药效学和药代动力学相互作用及其对手性药物药效学和药代动力学立体选择性的影响。     

临床药理学讲座 药效学与临床用药

药理学由药效动力学和药代动力学组成,主要研究药物与机体之间的相互作用。本文重点从药效动力学的角度阐述它与临床用药的关系。1 与药效学有关的基本理论1.1 何谓药效动力学 药效动力学(简称药效学)主要研究药物是如何影响人体的,即药物在人体产生的生理、生化效应及其机制。在理论上,它是药理学的理论基础;在实践上它可指导合理用药,发挥药物的最佳疗效,防止药物的不良反应。1.2 药物作用及作用机理     

基因治疗产品的生物分析：方法开发的策略

基因治疗产品采用独特的递送和治疗机制,评估其安全性和有效性需要设计并开发非传统和全面的生物分析方法。在临床前和临床生物分析研究涉及药代动力学、药效学、免疫原性、生物标志物分析等方面。基因治疗产品的药代动力学和药效学研究需要确定载体、目的基因、以及目的基因表达产物蛋白的存在、作用部位和生物分布。而对于免疫原性的研究,则需要监测机体针对基因治疗载体所产生的抗体,以及可能需要在接受治疗前评估受试者的预存抗体。由于基因治疗产品表达的外源产物蛋白也可能引发机体的免疫反应,因此针对表达产物的抗体也是免疫原性的研究内容。本文从药代动力学、药效学与免疫原性分析研究方向,综述基因治疗产品的生物分析方法开发的关键点、策略和实践。     

Primer on clinical pharmacokinetics

Basic concepts of clinical pharmacokinetics and principles of therapeutic drug monitoring are discussed. Pharmacokinetic variables such as volume of distribution, clearance, and half-life describe drug disposition in the body; in individual patients, these values may vary substantially. Serum concentrations of drugs may be influenced by numerous factors, such as route of administration, bioavailability, tissue distribution, and clearance. Therapeutic drug monitoring is designed to individualize drug dosages to achieve steady-state concentrations within a range of values that correlates well with patient response. An understanding of clinical pharmacokinetics and drug monitoring facilitates interpretation of serum concentrations in individual patients.     

Pharmacokinetic and pharmacodynamic considerations when treating patients with sepsis and septic shock

Sepsis and septic shock are accompanied by profound changes in the organism that may alter both the pharmacokinetics and the pharmacodynamics of drugs. This review elaborates on the mechanisms by which sepsis-induced pathophysiological changes may influence pharmacological processes. Drug absorption following intramuscular, subcutaneous, transdermal and oral administration may be reduced due to a decreased perfusion of muscles, skin and splanchnic organs. Compromised tissue perfusion may also affect drug distribution, resulting in a decrease of distribution volume. On the other hand, the increase in capillary permeability and interstitial oedema during sepsis and septic shock may enhance drug distribution. Changes in plasma protein binding, body water, tissue mass and pH may also affect drug distribution. For basic drugs that are bound to the acute phase reactant alpha(1)-acid glycoprotein, the increase in plasma concentration of this protein will result in a decreased distribution volume. The opposite may be observed for drugs that are extensively bound to albumin, as the latter protein decreases during septic conditions. For many drugs, the liver is the main organ for metabolism. The determinants of hepatic clearance of drugs are liver blood flow, drug binding in plasma and the activity of the metabolic enzymes; each of these may be influenced by sepsis and septic shock. For high extraction drugs, clearance is mainly flow-dependent, and sepsis-induced liver hypoperfusion may result in a decreased clearance. For low extraction drugs, clearance is determined by the degree of plasma binding and the activity of the metabolic enzymes. Oxidative metabolism via the cytochrome P450 enzyme system is an important clearance mechanism for many drugs, and has been shown to be markedly affected in septic conditions, resulting in decreased drug clearance. The kidneys are an important excretion pathway for many drugs. Renal failure, which often accompanies sepsis and septic shock, will result in accumulation of both parent drug and its metabolites. Changes in drug effect during septic conditions may theoretically result from changes in pharmacodynamics due to changes in the affinity of the receptor for the drug or alterations in the intrinsic activity at the receptor. The lack of valid pharmacological studies in patients with sepsis and septic shock makes drug administration in these patients a difficult challenge. The patient's underlying pathophysiological condition may guide individual dosage selection, which may be guided by measuring plasma concentration or drug effect.     

Drug interaction studies of therapeutic proteins or monoclonal antibodies

Drug interactions can alter the pharmacokinetics and/or pharmacodynamics of a drug. In pharmacokinetic drug interactions, the concentrations of 1 or more drugs are altered by another. This change in concentration in a given drug may be due to changes in absorption, distribution, metabolism, or elimination. The pharmacodynamic interaction can lead to additive, synergistic, or antagonistic effects of a drug. Drug interaction studies are regularly conducted with conventional drugs (small molecules), but very few drug interaction studies have been performed with macromolecules (therapeutic proteins or monoclonal antibodies). This is mainly because most macromolecules are not metabolized by the cytochrome P450 system, and their mechanism of elimination is complex. However, it has been shown in several studies that interferons can have an impact on the cytochrome P450 system that may alter the pharmacokinetics and pharmacodynamics of a conventional drug when given with interferons. Therefore, it is important to evaluate the effect of other classes of macromolecules (cytokines, interleukins, monoclonal antibodies) on drug-metabolizing enzymes. It is also imperative that the effects of conventional drugs on the pharmacokinetics and pharmacodynamics of macromolecules be conducted. The present review encompasses several drug interaction studies that were conducted with macromolecules and highlights the impact of these studies on the pharmacokinetics and/or pharmacodynamics of the involved drugs.     

Pharmacokinetics of rapamycin: single-dose studies in the rabbit.

The pharmacokinetics of rapamycin was investigated in five New Zealand white rabbits following intravenous administration of 0.05 and 0.5 mg/kg rapamycin in a randomized crossover fashion. Whole blood concentrations of rapamycin were analyzed by high-performance liquid chromatography (HPLC). Model-dependent and -independent parameters were calculated. The volume of distribution at steady state and total body clearance increased significantly as the dose increased. Rapamycin pharmacokinetics appear to be nonlinear. The whole blood volume of distribution, especially at the higher dose, indicated distribution out of the blood component. The drug is not cleared rapidly, with a terminal half-life of > 13 hours as calculated by model-independent parameters. The 24-h whole blood trough concentrations of the drug are well within the analytical range of the HPLC procedure. This should permit trough level monitoring for therapeutic range studies involving the drug.     

Biomedical accelerator mass spectrometry: recent applications in metabolism and pharmacokinetics

BACKGROUND: Accelerator mass spectrometry (AMS) is a sensitive isotope ratio technique used in drug development that allows for small levels of 14C-drug to be administered to humans, thereby removing regulatory hurdles associated with radiotracer studies. AMS uses innovative study designs to obtain pharmacokinetic and metabolism data. OBJECTIVE: This review addresses the metabolism and pharmacokinetics relevant to cases where therapeutic drug concentrations are achieved in humans. METHODS: The review focuses on two study designs: i) administration of tracer 14C-drug intravenously with a simultaneous non-labelled extravascular therapeutic dose to obtain the pharmacokinetic parameters of clearance, volume of distribution and absolute bioavailability without extensive intravenous toxicology safety studies or formulation development; and ii) use of low levels of 14C-drug during Phase I studies to investigate the quantitative metabolism of the drug in humans early in drug development, as required by the new FDA guideline issued in February 2008. RESULTS/CONCLUSIONS: Early knowledge about a drug's clearance, volume of distribution, absolute bioavailability and metabolism can affect the development of a new drug candidate.     

A systematic review on pharmacokinetic changes in critically ill patients: role of extracorporeal membrane oxygenation

Objective

Several factors including disease condition and different procedures could alter pharmacokinetic profile of drugs in critically ill patients. For optimizing patient''s outcome, changing in dosing regimen is necessary. Extracorporeal Membrane Oxygenation (ECMO) is one of the procedures which could change pharmacokinetic parameters.The aim of this review was to evaluate the effect of ECMO support on pharmacokinetic parameters and subsequently pharmacotherapy.

Method

A systematic review was conducted by reviewing all papers found by searching following key words; extracorporeal membrane oxygenation, ECMO, pharmacokinetic and pharmacotherapy in bibliography database.

Results

Different drug classes have been studied; mostly antibiotics. Almost all of the studies have been performed in neonates (as a case series). ECMO support is associated with altered pharmacokinetic parameters that may result in acute changes in plasma concentrations with potentially unpredictable pharmacological effect. Altreation in volume of distribution, protein binding, renal or hepatic clearance and sequestration of drugs by ECMO circuit may result in higher or lower doses requirement during ECMO. As yet, definite dosing guideline is not available.ECMO is extensively used recently for therapy and as a procedure affects pharmacokinetics profile along with other factors in critically ill patients. For optimizing the pharmacodynamic response and outcome of patients, drug regimen should be individualized through therapeutic drug monitoring whenever possible.     

Disease-induced changes in the plasma binding of basic drugs

The plasma binding of basic (cationic) drugs differs from that of the more completely studied acidic drugs. Basic drugs associate with a number of plasma constituents. alpha 1-Acid glycoprotein, lipoprotein, and albumin all appear to play an important role in the binding of most of these drugs. Acidic drugs bind largely to albumin. The variation in plasma albumin is relatively narrow and is almost always in the direction of decreased concentrations. alpha 1-Acid glycoprotein and lipoproteins show large fluctuations due both to physiological and pathological conditions. Decreases and increases in concentration have been observed. Associated with these changes in binding proteins, both decreases and increases in plasma binding of basic drugs have been recorded. Increased binding with disease appears to be virtually unique to basic drugs. The implications of these newly described disease-induced increases in plasma binding have yet to be explored. With the limited information in hand the following consequences are predicted. Increased binding will tend to decrease the volume of distribution of total (bound plus free) drug. The clearance will be unchanged or decreased depending upon the initial clearance of the drug and the avidity of the protein binding. As the half-life depends upon both clearance and volume of distribution, changes in it will be variable, depending upon changes in these two parameters. It is predicted that the area under the free drug plasma concentration-time curve will decrease with increasing binding after an intravenous dose while it will be unchanged after an oral dose. The relationship of total drug plasma concentration to free drug concentration will change with changes in binding. Thus plasma concentration monitoring of drug therapy by use of total drug concentrations will be inaccurate in situations in which large variations in binding occur. Misinterpretations of both therapeutic monitoring and pharmacokinetics studies in disease states with altered binding are likely unless these changes are appreciated.     

The effect of therapeutic hypothermia on drug metabolism and response: cellular mechanisms to organ function

INTRODUCTION: Therapeutic hypothermia is being employed clinically due to its neuro-protective benefits. Both critical illness and therapeutic hypothermia significantly affect drug disposition, potentially contributing to drug-therapy and drug-disease interactions. Currently, there is limited information on the known alterations in drug concentration and response during mild hypothermia treatment, and there is a limited understanding of the specific mechanisms that underlie alterations in drug concentrations and the potential clinical importance of these changes. AREAS COVERED: A systemic review of the effect of therapeutic hypothermia on drug metabolism, disposition and response is provided. Specifically, the clinical and preclinical evidence of the effects of therapeutic hypothermia on blood flow, specific hepatic metabolism pathways, transporter function, renal excretion, pharmacodynamics and the effects during rewarming are reviewed. EXPERT OPINION: Available evidence demonstrates that mild hypothermia decreases the clearance of a variety of drugs with apparently little change in drug-protein binding. Recent evidence suggests that the magnitude of the change is elimination route specific. Further research is needed to determine the impact of these alterations on both drug concentration and response in order to optimize the therapeutic hypothermia in this vulnerable patient population.     

Oseltamivir in seasonal, avian H5N1 and pandemic 2009 A/H1N1 influenza: pharmacokinetic and pharmacodynamic characteristics

Oseltamivir is the ester-type prodrug of the neuraminidase inhibitor oseltamivir carboxylate. It has been shown to be an effective treatment for both seasonal influenza and the recent pandemic 2009 A/H1N1 influenza, reducing both the duration and severity of the illness. It is also effective when used preventively. This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of this agent, and to address the issue of possible therapeutic drug monitoring. According to the currently available literature, the pharmacokinetics of oseltamivir carboxylate after oral administration of oseltamivir are characterized by mean ± SD bioavailability of 79 ± 12%, apparent clearance of 25.3 ± 7.0 L/h, an elimination half-life of 7.4 ± 2.5 hours and an apparent terminal volume of distribution of 267 ± 122 L. A maximum plasma concentration of 342 ± 83 μg/L, a time to reach the maximum plasma concentration of 4.2 ± 1.1 hours, a trough plasma concentration of 168 ± 32 μg/L and an area under the plasma concentration-time curve from 0 to 24 hours of 6110 ± 1330 μg · h/L for a 75 mg twice-daily regimen were derived from literature data. The apparent clearance is highly correlated with renal function, hence the dosage needs to be adjusted in proportion to the glomerular filtration rate. Interpatient variability is moderate (28% in apparent clearance and 46% in the apparent central volume of distribution); there is no indication of significant erratic or limited absorption in given patient subgroups. The in vitro pharmacodynamics of oseltamivir carboxylate reveal wide variation in the concentration producing 50% inhibition of influenza A and B strains (range 0.17-44 μg/L). A formal correlation between systemic exposure to oseltamivir carboxylate and clinical antiviral activity or tolerance in influenza patients has not yet been demonstrated; thus no formal therapeutic or toxic range can be proposed. The pharmacokinetic parameters of oseltamivir carboxylate after oseltamivir administration (bioavailability, apparent clearance and the volume of distribution) are fairly predictable in healthy subjects, with little interpatient variability outside the effect of renal function in all patients and bodyweight in children. Thus oseltamivir carboxylate exposure can probably be controlled with sufficient accuracy by thorough dosage adjustment according to patient characteristics. However, there is a lack of clinical study data on naturally infected patients. In addition, the therapeutic margin of oseltamivir carboxylate is poorly defined. The usefulness of systematic therapeutic drug monitoring in patients therefore appears to be questionable; however, studies are still needed to extend the knowledge to particular subgroups of patients or dosage regimens.     

Protein binding of glycopeptide antibiotics with diverse physical-chemical properties in mouse, rat, and human serum

In previous studies of the pharmacokinetics and urinary excretion of nine glycopeptides with diverse isoelectric points (pI), as pI decreases, the total systemic and renal clearance, urinary recovery, and volume of distribution decrease, whereas the half-life increases. With glycopeptides of similar pI, clearance decreases and half-life increases with increasing lipophilicity. The present study examines the serum protein binding of these glycopeptide antibiotics in mouse, rat, and human serum and calculates the previously reported pharmacokinetic parameters for these drugs based on unbound concentration. Increased negative charge and lipophilicity increase serum protein binding (90-fold, fu 83% to 0.96%), which decreases the renal clearance and total systemic clearance (90-fold, 16.4 to 0.18 ml/min/kg) of these drugs. Increased serum protein binding also decreases the volume of distribution of these compounds, but this change is relatively small (sixfold, 755 to 131 ml/kg) compared with the change in total systemic clearance causing an increase in elimination half-life (25-fold, 20 to 492 min). The results demonstrate that the large differences in the total systemic clearance and half-life of these glycopeptide antibiotics are primarily due to dramatic differences in serum protein binding and not to differences in the intrinsic elimination processes (enzymes or transport proteins). It appears that the same physical-chemical properties that govern the protein binding and pharmacokinetics of small organic molecules govern the disposition of these high-molecular weight glycopeptide antibiotics.