Interspecies allometric meta‐analysis of the comparative pharmacokinetics of 85 drugs across veterinary and laboratory animal species

Allometric scaling is widely used for the determination of first dosage regimen and the interpolation or extrapolation of pharmacokinetic parameters across many animal species during drug development. In this article, 85 drugs used in veterinary medicine obtained from the Food Animal Residue Avoidance Databank database were selected for allometric scaling analysis. Outlier species were identified by statistical methods. The results showed that 77% and 88% of drugs displayed significant correlations between total systemic clearance (CL) and volume of distribution at steady status (Vss) vs. body weight (P < 0.05) on a log‐log scale, respectively. The distribution of the allometric exponent b for CL and Vss displays approximate normal distribution, with means (0.87 and 0.99) and standard deviations (0.143 and 0.157) for CL and Vss, respectively. Twelve drugs were identified to have at least one outlier species for CL and ten drugs for Vss. The human CL and Vss were predicted for selected drugs by the obtained allometric equations. The predicted CL and Vss were within a threefold error compared to observed values, except the predicted CL values for antipyrine, warfarin and diazepam. The results can be used to estimate cross‐species pharmacokinetic profiles for predicting drug dosages in veterinary species, and to identify those species for which interpolation or extrapolation of pharmacokinetics properties may be problematic.     

Pharmacodynamics and pharmacokinetics of nonsteroidal anti-inflammatory drugs in species of veterinary interest

This review summarises selected aspects of the pharmacokinetics (PK) and pharmacodynamics (PD) of nonsteroidal anti-inflammatory drugs (NSAIDs). It is not intended to be comprehensive, in that it covers neither minor species nor several important aspects of NSAID PD. The limited objective of the review is to summarise those aspects of NSAID PK and PD, which are important to an understanding of PK-PD integration and PK-PD modelling (the subject of the next review in this issue). The general features of NSAID PK are: usually good bioavailability from oral, intramuscular and subcutaneous administration routes (but with delayed absorption in horses and ruminants after oral dosing), a high degree of binding to plasma protein, low volumes of distribution, limited excretion of administered dose as parent drug in urine, marked inter-species differences in clearance and elimination half-life and ready penetration into and slow clearance from acute inflammatory exudate. The therapeutic effects of NSAIDs are exerted both locally (at peripheral inflammatory sites) and centrally. There is widespread acceptance that the principal mechanism of action (both PD and toxicodynamics) of NSAIDs at the molecular level comprises inhibition of cyclooxygenase (COX), an enzyme in the arachidonic acid cascade, which generates inflammatory mediators of the prostaglandin group. However, NSAIDs possess also many other actions at the molecular level. Two isoforms of COX have been identified. Inhibition of COX-1 is likely to account for most of the side-effects of NSAIDs (gastrointestinal irritation, renotoxicity and inhibition of blood clotting) but a minor contribution also to some of the therapeutic effects (analgesic and anti-inflammatory actions) cannot be excluded. Inhibition of COX-2 accounts for most and possibly all of the therapeutic effects of NSAIDs. Consequently, there has been an intensive search to identify and develop drugs with selectivity for inhibition of COX-2. Whole blood in vitro assays are used to investigate quantitatively the three key PD parameters (efficacy, potency and sensitivity) for NSAID inhibition of COX isoforms, providing data on COX-1:COX-2 inhibition ratios. Limited published data point to species differences in NSAID-induced COX inhibition, for both potency and potency ratios. Members of the 2-arylpropionate sub-groups of NSAIDs exist in two enantiomeric forms [R-(-) and S-(+)] and are licensed as racemic mixtures. For these drugs there are marked enantiomeric differences in PK and PD properties of individual drugs in a given species, as well as important species differences in both PK and PD properties.     

Interspecies allometric scaling: prediction of clearance in large animal species: part II: mathematical considerations

Interspecies scaling is a useful tool for the prediction of pharmacokinetic parameters from animals to humans, and it is often used for estimating a first-time in human dose. However, it is important to appreciate the mathematical underpinnings of this scaling procedure when using it to predict pharmacokinetic parameter values across animal species. When cautiously applied, allometry can be a tool for estimating clearance in veterinary species for the purpose of dosage selection. It is particularly valuable during the selection of dosages in large zoo animal species, such as elephants, large cats and camels, for which pharmacokinetic data are scant. In Part I, allometric predictions of clearance in large animal species were found to pose substantially greater risks of inaccuracies when compared with that observed for humans. In this report, we examine the factors influencing the accuracy of our clearance estimates from the perspective of the relationship between prediction error and such variables as the distribution of body weight values used in the regression analysis, the influence of a particular observation on the clearance estimate, and the 'goodness of fit' (R(2)) of the regression line. Ultimately, these considerations are used to generate recommendations regarding the data to be included in the allometric prediction of clearance in large animal species.     

Allometric analysis of ciprofloxacin and enrofloxacin pharmacokinetics across species

The purpose of this study was to examine the allometric analysis of ciprofloxacin and enrofloxacin using pharmacokinetic data from the literature. The pharmacokinetic parameters used were half-life, clearance and volume of distribution. Relationships between body weight and the pharmacokinetic parameter were based on the empirical formula Y = aW(b), where Y is half-life, clearance or volume of distribution, W the body weight and a is an allometric coefficient (intercept) that is constant for a given drug. The exponential term b is a proportionality constant that describes the relationship between the pharmacokinetic parameter of interest and body weight. A total of 21 different species of animals were studied. Results of the allometric analyses indicated similarity between clearance and volume of distribution as they related to body weight for both drugs. Results of the current analyses indicate it is possible to use allometry to predict pharmacokinetic variables of enrofloxacin or ciprofloxacin based on body size of species. This could provide information on appropriate doses of ciprofloxacin and enrofloxacin for all species.     

Comparison of the pharmacokinetics of five aminoglycoside and aminocyclitol antibiotics using allometric analysis in mammal and bird species

The allometric equations relating the half-life, the volume of distribution and the total body clearance of gentamicin, amikacin, tobramycin, kanamycin and apramycin to body weight for mammalian and mammalian + avian species were defined. Literature data were used as a source of comparative pharmacokinetic data. For all antibiotics examined half-life intercepts ranged from 0.49 to 1.66, slopes from 0.05 to 0.45, volume of distribution intercepts--0.13-0.75, slope-- 0.77-1.41, total body clearance intercepts--0.88-8.8 and slope--0.62-1.04. A better relationship between pharmacokinetic parameters and body weight was shown when all values were included in the allometric analysis. Different values of intercept and slope between birds and mammals were found in gentamicin and apramycin studies. In some cases, slopes and intercepts changed when all values of pharmacokinetic parameters were included. We conclude that small difference exist between pharmacokinetics of gentamicin, amikacin, tobramycin, kanamycin and apramycin. The allometric equations shown in our study provide a basis to estimate dose intervals for mammals and birds for which specific information is lacking.     

基于非线性混合效应模型分析兽药药代动力学研究进展

利用数学建模分析兽药药代动力学历来已久。兽药药代动力学中应用数学建模和模拟分析可简化和加快兽药研发进程。非线性混合效应模型分析方法是兽药药代动力学建模和模拟的主要方法之一,该方法对临床合理用药、新药研发及评审更高效具有很大意义,同时阐明一些传统药动学无法回答的问题。本文综述了非线性混合效应模型在分析兽药药代动力学主要原理及应用进展,以期望非线性混合效应模型分析方法在我国新兽药研发与评审中应用提供积极有益的参考。     

加强兽药监管促进养殖业发展

针对长沙市兽药、兽药残留的现状和危害，本文指出应从抓源头管理、建立市场准入制度和完善保障体系等三个方面加强兽药监管，介绍了监管工作取得的阶段性成果，提出了今后进一步加强兽药监管的思路和建议。     

Interspecies differences in the pharmacokinetics of kanamycin and apramycin

Comparative studies on some selected pharmacokinetic parameters for kanamycin in sheep, goats, rabbits, chickens and pigeons, and for apramycin in sheep, rabbits, chickens and pigeons were carried out after intravenous administration of the two drugs at a dose of 10 mg/kg. The results revealed that a two-compartment open model was most suitable for kanamycin, while for apramycin a one-compartment open model was usually optimal. The log distribution rate constant (alpha) of kanamycin was significantly correlated to the log of the body mass (r = 0.919, n = 5, p < 0.05). Interspecies differences in the apparent volume of distribution (Vda) of kanamycin were small. These differences were larger for apramycin, as were the variations in the area under the serum concentration-time curve (AUC) and in the total body clearance (ClB) of both kanamycin and apramycin, both having almost a threefold difference depending on the species but without any correlation to body mass. The values of the log half-life of kanamycin in the mammals in this study and also those from data in the literature revealed a significant correlation with log body mass between animal species according to the equation: t1/2 beta = 38.47W0.21 (r = 0.7648, n = 10, p < 0.05).     

The pharmacokinetics and metabolism of ivermectin in domestic animal species

The pharmacokinetic properties of drugs are closely related to their pharmacological efficacy. The kinetics of ivermectin are characterised, in general terms, by a slow absorption process, a broad distribution in the organism, low metabolism, and slow excretion. The kinetics vary according to the route of administration, formulation, animal species, body condition, age, and physiological status, all of which contribute to differences in drug efficacy. Characterisation of ivermectin kinetics can be used to predict and optimise the value of the parasiticide effects and to design programmes for parasite control. This article reviews the pharmacokinetics of ivermectin in several domestic animal species.     

我国兽药生产企业现状及产品开发思路的探讨

简述我国兽药生产企业目前的现状，提出了产品开发的方向，应注重原料药、西药复方制剂、兽药制剂新剂型、天然药物和生物制剂的开发。     

打击假劣兽药保护畜牧业生产健康发展

介绍了近年来山东省打击假劣兽药采取的一些措施,分析了制售假劣兽药的新动向、新特点以及打假过程中存在的一些问题,认为应当加强兽药监督执法体系建设,为兽药打假工作提供组织和技术保证,强化监督、依法打击制售假劣兽药活动.当前应当认清形势,抓住重点难点问题,不断总结经验,改进工作方法,采取有力措施,加强兽药生产监管,规范市场,开创兽药打假工作新局面.     

Modeling and allometric scaling of s(+)-ketoprofen pharmacokinetics and pharmacodynamics: a retrospective analysis

Interspecies scaling of pharmacokinetic (PK) parameters is commonplace in drug development. However, information about proportionality of pharmacodynamic (PD) parameters in different species is scarce. We investigated the feasibility of allometric scaling of PK and PD parameters of s(+)-ketoprofen (sKTP) using the literature data from several animal species. Two different indirect response models were proposed to characterize sKTP inhibitory effects on synthesis of thromboxane B(2) (TXB(2)) and prostaglandin E(2) (PGE(2)). Using the traditional allometric approach, the obtained PK and PD parameters were plotted against body weights (BW) on a log-log scale. For all species, values of systemic clearance (Cl), distribution clearance (Cl(D)), central volume of distribution (V(c)), and volume of distribution at steady-state (V(ss)) were highly correlated (r(2) = 0.89-0.99) with BW. The PD parameters for inhibition of TXB(2) synthesis were poorly correlated with BW (r(2) = 0.25-0.54) while most of the parameters for inhibition of PGE(2) synthesis lacked any correlation (r(2) approximately 0.05). In conclusion, indirect response models adequately described the time course of sKTP inhibitory effects on synthesis of TXB(2) and PGE(2). Allometrical scaling showed PK parameters to change proportionally to BW, whereas PD parameters had limited ranges and were essentially weight independent.     

The scope of a laboratory animal program needed at a veterinary school.

The discipline of laboratory animal medicine is one of the most rapidly expanding specialties within the veterinary profession. Veterinary schools should fully accept the responsibility for introductory instruction in laboratory animal medicine in the professional curriculum. Such instruction should articulate the varied opportunities that exist for the laboratory animal veterinarian within the biomedical research community, and provide an overview of the normal biological characteristics and pathologic conditions of the common laboratory animal species. In addition, the opportunity should exist within the veterinary school for graduate and undergraduate students utilizing experimental animals to receive a comprehensive introduction to laboratory animal biology, care, and management. Instructional responsibility for such courses should be accepted by faculty veterinarians with advanced training in laboratory animal medicine. Veterinarians with advanced training in this specialty are uniquely qualified to make substantial contributions to biomedical research by promoting the health and welfare of the research animal.     

提高对兽药的认知深度,促进动物保健品行业的健康发展

兽药是动物保健品行业的主业,是行业中最重要的组成部分.为社会提供绿色、健康食品需要我们兽药生产企业加深对兽药及整个动物保健品行业的认知度,为养殖业提供高效、安全的兽药产品,国务院新修订的〈兽药管理条例〉以及农业部制定的一系列〈兽药管理条例〉的配套行政规章都要求我们要加强对兽药的法制化管理,规范兽药的市场行为,促进兽药行业的健康发展,为人类健康和公共卫生服务.为了这一目标的实现,企业界和管理部门都做出了巨大的努力,形成了今天这种良好的局面.我们要走的路还很长,要做的工作还很多.行业要发展,企业要做强,市场要规范,产品质量要上新台阶,这一切都要靠业内全体同仁的不懈努力.我们要认清肩负的历史责任,明确发展方向,克服前进中的困难,改进工作中的不足,将我们的行业推向一个新的发展阶段.在这里,我就如何提高对兽药行业和兽药监管工作的认识,如何充分发挥行业协会的重要作用,促进行业的健康发展,谈点个人的认识和看法,与大家共同探讨.不妥之处,请批评指正。     

对我国动物源性食品中兽药残留问题的思考

二十世纪90年代以来,我国政府和有关部门对解决动物源性食品中兽药残留问题做了大量的工作,如制订“兽药残留标准检测方法”和“兽药最高残留限量和休药期”的标准,发布《饲料药物添加剂使用规范》,开展兽药残留监控和检测工作,打击、查处在动物生产中使用违禁药物等措施,并取得了明显的成绩,使我国动物源性食品中兽药残留的问题得到了明显的改善。但是,近年来我国动物源性食品在基本满足了数量要求以后,随着人民生活水平的提高,对食品的质量安全的要求已成为主要的问题,人民都要求吃上“放心肉”、“安全肉”,在这方面目前的现状尚有一定的…