Pharmacology in space. Part 1. Influence of adaptive changes on pharmacokinetics

The topic of pharmacology in space, i.e. the administration of drugs during space flight and the subsequent pharmacokinetic handling of the pharmaceuticals, is a new field about which little is known. In a two-part series, Claire Lathers and colleagues highlight some of the current questions in this field. In this first article the physiological and biochemical changes associated with weightlessness in space are discussed. These changes induce adaptive alterations which may influence the pharmacokinetic properties of drugs. The cardiovascular system is of particular relevance here. Also discussed are the classes of pharmacological agent that are most likely to be used during space flight for medical problems and thus, by necessity, will become drugs to be examined in space to determine whether their pharmacokinetic and pharmacodynamic properties are altered. Therapy of the most common spaceflight ailment-motion sickness-will be considered next month in Part 2.     

Paying attention to pharmacokinetic and pharmacodynamic mechanisms to progress in the area of anticholinergic use in geriatric patients

Many naturalistic studies agree that adverse drug reactions (ADRs), particularly cognitive deficits, frequently occur when medications with anticholinergic activity are used in geriatric patients. However, the studies disagree on which anticholinergic drugs may have clinical relevance. The three most important methods to establish clinically relevant anticholinergic activity are: 1) the drug's affinity for muscarinic receptors, demonstrated by in vitro studies and a profile compatible with antagonist properties; 2) serum anticholinergic activity measured by radioreceptor assay; and 3) the presence of typical antimuscarinic ADRs, such as dry mouth and constipation, in patient studies or clinical trials. More recently, brain imaging of muscarinic receptors and scales for quantifying antimuscarinic activity were developed. A comprehensive approach can be crafted only by paying attention to the pharmacodynamic and pharmacokinetic mechanisms of these drugs. ADR studies on drugs with anticholinergic activity should not only consider central muscarinic receptor blockade, but also peripheral receptor blockade. The ability to cross the blood-brain barrier is important in the drug's ADR profile. Patient personal characteristics, drug-drug interactions (DDIs) and probably genetic variations may contribute to increased ADR risk through pharmacokinetic and/or pharmacodynamic mechanisms. Sophisticated clinical designs and the evidence-based medicine approach cannot succeed unless the list of drugs of anticholinergic activity is agreed upon, and the studies include a sophisticated pharmacological approach guided by our current understanding of their pharmacodynamic and pharmacokinetic mechanisms. If one agrees that antimuscarinic ADRs are probably dose-related, future studies must consider all drugs, administration routes, doses, muscarinic receptor affinity, DDIs, and brain access.     

聚乙二醇修饰小分子药物的研究进展

聚乙二醇修饰技术是目前药物化学修饰的研究热点,它能够显著提高药物分子水溶性,同时改善药物的药动学和药效学特性,增加了药物临床应用的范围和疗效,具有较好的开发应用前景;但同时也存在诸多问题,有待改进,目前在国内研究相对较少,值得进一步研究开发。本文从聚乙二醇修饰技术被修饰的小分子药物种类、连接臂类型、聚乙二醇载体以及修饰后药物药动学性质和药效学性质改变等方面进行系统综述。     

Is there a role for therapeutic drug monitoring of new anticonvulsants?

Despite the fact that all new anticonvulsants have undergone extensive pharmacokinetic scrutiny prior to their introduction to the market, the opportunity to perform good prospective studies on their concentration-effect relationship has been largely missed, in some cases deliberately because therapeutic drug monitoring (TDM) is considered unfavourable for the marketing of a new drug. However, there are reasons to believe that TDM may play a useful role in maximising the therapeutic potential of new anticonvulsants. In fact, these drugs have a narrow therapeutic index, careful individualisation of dosage to optimise response is required, and inter- and intra-individual pharmacokinetic variability may translate into differences in dosage requirements. The wide interindividual variability in the serum concentrations at which therapeutic and toxic effects of these drugs are observed does not necessarily imply that TDM cannot be useful: indeed, a marked pharmacodynamic variability has also been reported for all the currently monitored older anticonvulsants. The new anticonvulsants which, based on their properties, are particularly attractive candidates for TDM include lamotrigine, topiramate, tiagabine, zonisamide and felbamate. However, in the absence on sound information on the target concentration ranges of these drugs, the routine concentration monitoring of these drugs cannot be recommended. Despite this, serial measurements of serum drug concentrations may be useful in selected patients, especially those suspected of poor compliance and those in whom pharmacokinetic changes caused by disease or administration of concomitant medication are anticipated. Even in the presence of marked interindividual pharmacodynamic variability, it is often possible to empirically determine the concentration at which each patient exhibits the best response, and apply that information in subsequent management. Prospective studies, using preferably a randomised concentration-controlled design, are necessary to better characterise concentration-effect relationships for these agents.     

Age-associated pharmacodynamic changes

Many pharmacodynamic changes with age have been identified. Quite likely, they, in concert with age-associated pharmacokinetic changes and multiple drug use, are responsible for altered drug action in the elderly and an increasing incidence of adverse drug reactions with age. The pharmacodynamic changes, which can result in altered action of important drugs, can lead to major adverse clinical outcomes if not recognized, particularly in those drugs which affect the heart and the central nervous system.     

微透析技术在抗菌药物药动学和药效学中的应用

微透析技术是一项新兴的体内药物分析技术。通过微透析技术与药动学和药效学模型结合,实现对组织或细胞外游离态药物浓度及其相应药理效应的同时研究,不仅有利于进一步明确药物的剂量-效应关系,制定临床最佳给药方案,而且也为个体化给药提供了科学依据。本文综合近年文献,对微透析技术的基本原理以及在抗菌药物药动学和药效学研究中的应用作一综述。     

Adaptive control methods for the dose individualisation of anticancer agents

Numerous studies have found a clear relationship between systemic exposure and the toxicity or (more rarely) the efficacy of anticancer agents. Moreover, the clearance of most of these drugs differs widely between patients. These findings, combined with the narrow therapeutic index of anticancer drugs, suggest that patient outcome would be improved if doses were individualised to achieve a target systemic exposure. Bayesian maximum a posteriori probability (MAP) forecasting is an efficient and robust method for the optimisation of drug therapy, but its use for anticancer drugs is not yet extensive. The aim of this paper is to review the application of population pharmacokinetics and MAP to anticancer drugs and to evaluate whether and when MAP Bayesian estimation improves the clinical benefit of anticancer chemotherapy. For each drug, the relationships between pharmacokinetic variables [e.g. plasma concentration or the area under the concentration-time curve] and pharmacodynamic effects are described. Secondly, the methodologies employed are considered and, finally, the results are analysed in terms of predictive performance as well as, where possible, the impact on clinical end-points. Some studies were retrospective and intended only to evaluate individual pharmacokinetic parameter values using very few blood samples. Among the prospective trials, a few studied the pharmacokinetic/pharmacodynamic relationships which provided the basis for routine pharmacokinetic monitoring. Others were performed in clinical context where MAP Bayesian estimation was used to determine maximum tolerated systemic exposure (e.g. for carboplatin, topotecan, teniposide) or for pharmacokinetic monitoring (e.g. for methotrexate or platinum compounds). Indeed, its flexibility in blood sampling times makes this technique much more applicable than other limited sampling strategies. These examples demonstrate that individual dose adjustment helps manage toxicity. The performance of pharmacokinetic monitoring is linked to the methodology used at each step of its design and application. Moreover, a limitation to the use of pharmacokinetic monitoring for certain anticancer drugs has been the difficulty in obtaining pharmacokinetic or pharmacodynamic data. Recent progress in analytical methods, as well as the development of noninvasive methods (such as positron emission tomography) for evaluating the effects of chemotherapy, will help to define pharmacokinetic-pharmacodynamic relationships. Bayesian estimation is the strategy of choice for performing pharmacokinetic studies, as well as ensuring that a given patient benefits from the desired systemic exposure. Together, these methods could contribute to improving cancer chemotherapy in terms of patient outcome and survival.     

Population pharmacokinetic-pharmacodynamic modelling of angiotensin receptor blockade in healthy volunteers

OBJECTIVE: To compare the pharmacokinetic and pharmacodynamic characteristics of angiotensin II receptor antagonists as a therapeutic class. DESIGN: Population pharmacokinetic-pharmacodynamic modelling study. METHODS: The data of 14 phase I studies with 10 different drugs were analysed. A common population pharmacokinetic model (two compartments, mixed zero- and first-order absorption, two metabolite compartments) was applied to the 2685 drug and 900 metabolite concentration measurements. A standard nonlinear mixed effect modelling approach was used to estimate the drug-specific parameters and their variabilities. Similarly, a pharmacodynamic model was applied to the 7360 effect measurements, i.e. the decrease of peak blood pressure response to intravenous angiotensin challenge recorded by finger photoplethysmography. The concentration of drug and metabolite in an effect compartment was assumed to translate into receptor blockade [maximum effect (Emax) model with first-order link]. RESULTS: A general pharmacokinetic-pharmacodynamic (PK-PD) model for angiotensin antagonism in healthy individuals was successfully built up for the 10 drugs studied. Representatives of this class share different pharmacokinetic and pharmacodynamic profiles. Their effects on blood pressure are dose-dependent, but the time course of the effect varies between the drugs. CONCLUSIONS: The characterisation of PK-PD relationships for these drugs gives the opportunity to optimise therapeutic regimens and to suggest dosage adjustments in specific conditions. Such a model can be used to further refine the use of this class of drugs.     

Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam

This review was conducted to identify the current data on drug interactions with alprazolam, midazolam, and triazolam to guide practitioners in the use of these drugs. The Medline electronic database from 1966 through 1998 was used to identify clinical studies of the pharmacokinetic effect of drugs on these three benzodiazepines. Of a total of 491 literature reports identified, 59 prospective studies met our selection criteria. The pharmacokinetic parameters of AUC, Cmax, t1/2, and tmax were evaluated for changes following an interaction. To allow comparison between studies, changes in the parameters were normalized relative to the control values. Pharmacodynamic effects and measures, when reported in the original studies as statistically significant, were classified as a strong interaction, and when the interaction was present but not statistically significant, they were classified as mild in this review. As a result, clinically significant drug interactions were noted for all three benzodiazepines, although it is clear that statistically significant pharmacokinetic changes do not always translate into clinically significant pharmacodynamic consequences. All three benzodiazepines were susceptible to drug interactions, but oral dosing of midazolam and triazolam resulted in greater alterations in the pharmacokinetic parameters than alprazolam due to their larger presystemic extraction. Ketoconazole and itraconazole were found to be the most potent metabolic inhibitors that prolonged the duration of or intensified the magnitude of the dynamic response produced by the three benzodiazepines. Rifampin, carbamazepine, and phenytoin were noted to be potent metabolic inducers, and their treatments result in loss of benzodiazepine therapeutic efficacy. In conclusion, potent metabolic inhibitors and inducers can either significantly prolong or diminish the dynamic effects of benzodiazepines via their influence on the pharmacokinetics of benzodiazepines.     

手性药物的对映体选择性与临床应用

目的 :探讨临床应用手性药物的对映体选择性问题。方法 :从手性药物的药动学特性、药效学特性及临床应用几方面举例说明。结果与结论 :手性药物对映体表现出错综复杂的药代动力学和药效学特征。手性药物对映体的深入研究 ,将对临床合理应用手性药物产生深远的影响     

Animal model pharmacokinetics and pharmacodynamics: a critical review

Animals have been extensively used in the evaluation of antimicrobials. The value of animals in the pharmacokinetic and pharmacodynamic characterization of antimicrobials is critically reviewed. Animal studies have demonstrated that the pharmacokinetic/pharmacodynamic (PK/PD) target determining efficacy can vary for different classes of antimicrobials. However, the magnitude of the target required for bacteriological efficacy is relatively similar for various sites of infection, various pathogens and various drugs within the same class, provided free drug levels are used.     

连续性肾脏替代治疗中抗菌药物剂量的调整

由于接受连续性肾脏替代治疗（CRRT）的危重患者体内病理生理学的改变,抗菌药物的药动学和药效学参数会发生较大变化,因而最终影响了抗菌药物的效能。本文综述CRRT时影响药物清除的主要因素,并提出CRRT患者使用抗菌药物的剂量建议,为临床合理用药提供参考。     

Intravenous anaesthetic agents. Pharmacokinetic-pharmacodynamic relationships

The number and variety of intravenous anaesthetics available has increased dramatically in recent years. In order to administer these agents safely and rationally in the operating theatre, the anaesthesiologist needs to have a detailed understanding of their dose-response behaviour. The pharmacokinetic and pharmacodynamic profiles of these anaesthetics underlie this behaviour. In understanding and applying this information, an integrated approach involving combined pharmacokinetic and pharmacodynamic modelling has proved tremendously helpful. This approach has provided significant insight into the pharmacology of these drugs under conditions of normal and abnormal physiology. Intravenous anaesthetics may be classified as hypnotics, narcotics, or muscle relaxants. Through quantitative measures or drug effect, as provided by the electroencephalogram (EEG) in the former two classes or electromyography in the latter class, precise measures of end-organ (brain or neuromuscular junction) sensitivity have been generated using integrated modelling techniques. These values not only allow for dose potency comparisons within an anaesthetic class but, furthermore, may explain changes in drug response with ageing and disease. Incorporation within these models of an effect compartment, characterised by a rate constant for equilibration with plasma (keo), has proved to be essential in accurately describing the temporal lag between drug administration and effect. Quantitating the size of this lag has direct implications for the design of anaesthetic bolus and infusion regimens. Combined pharmacokinetic and pharmacodynamic modelling of intravenous anaesthetics provides a precise, rational basis for the clinical use of these classes of drugs.     

Cardiovascular drug therapy in elderly patients: specific age-related pharmacokinetic, pharmacodynamic and therapeutic considerations

An increasing number of elderly patients are exposed to cardiovascular drugs for the treatment of acute and/or chronic conditions. This is a result of the progressive aging of the population, a common feature in most industrialised countries, and an improvement in primary and secondary cardiovascular prevention strategies with increased survival rates. Traditionally, most elderly patients receiving cardiovascular drugs had advanced cardiac, liver and kidney disease that significantly influenced drug pharmacokinetic and pharmacodynamic parameters. Currently, however, many patients without significant organ impairment receive cardiovascular therapy for primary or early secondary prevention (i.e. increased vascular risk, asymptomatic left ventricular dysfunction, poststroke phase, type 2 diabetes mellitus), highlighting the need for a better understanding of specific age-related pharmacokinetic and pharmacodynamic effects. A systematic review has been conducted on the specific effects of aging, in the absence of major co-morbidities, on the pharmacokinetic and pharmacodynamic properties of traditional and newer cardiovascular drugs. Currently, the evidence available is poor or nonexisting for several drugs and mainly derived from very small and underpowered studies, thus limiting data interpretation. In particular, there is very little information on patients >80 years of age, thus raising important concerns about the correct use of these drugs in this constantly growing population.     

Using pharmacokinetics in drug therapy. IV: Consideration in applying pharmacokinetic and pharmacodynamic estimates to antihypertensive dosage regimens.

A theory explaining the pharmacokinetics of drugs with direct and rapidly reversible pharmacologic effects is reviewed, and the application of this theory to individualizing dosage regimens for antihypertensive drugs is discussed. In a few studies, investigators have correlated, under controlled conditions and in a small number of patients, the pharmacokinetic variables needed to individualize minoxidil and clonidine dosage regimens with clinical responses (mean arterial blood pressure). The potential clinical application of these correlations to other antihypertensive drugs was studied by retrospectively analyzing diastolic and mean arterial blood pressure data reported in 26 published studies of seven antihypertensive drugs. The wide interpatient variation recorded in the dose-response plots derived from the published data yielded pharmacodynamic values of little reliability or predictive value in individualizing antihypertensive dosage regimens. Use of retrospective data analysis for obtaining the necessary pharmacokinetic values to individualize antihypertensive dosage regimens is discouraged.     

Maternal-fetal transport of hypoglycaemic drugs

Due to legal, ethical and monetary problems, drug studies in pregnancy are rare. Numerous pharmacokinetic and pharmacodynamic changes occur in pregnancy that can affect the efficacy and safety of drugs, and these are difficult to predict without appropriate studies. Drugs potentially useful and safe in pregnancy have to either not cross the placenta and/or be harmless to the fetus at clinically relevant concentrations. The first characteristic can be predicted using in vitro models such as the placenta perfusion model. In the case of glibenclamide (glyburide), in vitro experiments showed minimal maternal-fetal transfer, leading to completion of a successful clinical trial of this drug in gestational diabetes. Insulin, the main drug used in diabetes during pregnancy, has also been shown not to cross the placenta in vitro, as has insulin lispro. Animal insulin may cross the placenta when complexed with anti-insulin antibodies. Other sulphonylurea drugs (tolbutamide and chlorpropamide) have been shown to cross the placenta both in vitro and in vivo and to produce toxicity in the fetus. This review summarises the pharmacokinetic data available for hypoglycaemic drugs during pregnancy, as well as the potential role for the in vitro placenta perfusion model in the preclinical evaluation of drugs with potential usefulness in pregnancy.     

Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications

Advancing age is characterized by impairment in the function of the many regulatory processes that provide functional integration between cells and organs. Therefore, there may be a failure to maintain homeostasis under conditions of physiological stress. The reduced homeostatic ability affects different regulatory systems in different subjects, thus explaining at least partly the increased interindividual variability occurring as people get older. Important pharmacokinetic and pharmacodynamic changes occur with advancing age. Pharmacokinetic changes include a reduction in renal and hepatic clearance and an increase in volume of distribution of lipid soluble drugs (hence prolongation of elimination half-life) whereas pharmacodynamic changes involve altered (usually increased) sensitivity to several classes of drugs such as anticoagulants, cardiovascular and psychotropic drugs. This review focuses on the main age-related physiological changes affecting different organ systems and their implications for pharmacokinetics and pharmacodynamics of drugs.     

苦参碱及氧化苦参碱的药代动力学与药效动力学

以QTc延长率为效应指标,用药代动力学-药效动力学结合模型对苦参碱、氧化苦参碱iv后在免体内的处置和效应动力学作定量分析,两药的血浓时程均符合二房室模型,两药的效应与效应室浓度之间的关系均符合S形E_max模型。两药彼此的药动学和药效学性质均有明显差异,但它们各自的劳动学和药效学性质在所用剂量范围内均为非剂量依赖性。     

Review: interactions between H2-antagonists and non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are being prescribed increasingly with an H2-antagonist. This article reviews those published studies which have examined the potential for pharmacokinetic and, where appropriate, pharmacodynamic interactions between these classes of drugs. Studies involving the administration of a single dose of a NSAID to young healthy volunteers are of limited relevance in establishing the likely effect of an H2-antagonist on the blood concentrations of an NSAID in patients. Appropriate studies are those which will examine the effects of H2-antagonists on the steady-state pharmacokinetics of NSAIDs in patients with inflammatory joint diseases. More of such studies are required, particularly involving elderly patients.     

Pharmacodynamics and population pharmacokinetics of enalapril and lisinopril

The di-acid metabolite of enalapril, enalaprilat, and its lysine analogue lisinopril are potent inhibitors of angiotensin converting enzyme (ACE); they do not contain sulphydryl groups. Both drugs can be assayed by high pressure liquid chromatography and by radioimmunoassay and plasma ACE inhibition remains stable under normal storage conditions. It is therefore possible to study their pharmacokinetics as well as their pharmacodynamic effects in man. Enalaprilat and lisinopril as well as ACE activity have been measured in blood taken during the course of two studies of the effects of these drugs on blood pressure and autonomic responsiveness. A population pharmacokinetic analysis approach applied to a few concentration-time data points in each of a relatively large number of subjects provided average population parameter estimates of the absorption rate constant, volume of distribution and clearance which correspond closely with the limited published data based on conventional pharmacokinetic approaches. It also provided estimates of pharmacodynamic parameters and the concentration of the drug required to produce a 50% ACE inhibition. Population drug concentration data obtained in the course of early clinical evaluations of new drugs may provide a rational basis for dosage regimens with improved efficacy and, in particular, reduced concentration-related toxic effects.