Challenges obtaining a biowaiver for topical veterinary dosage forms

Obtaining a biowaiver for topical drugs used in veterinary species faces many of the same challenges associated with human topicals. However, the skin of domestic animals varies anatomically and biochemically and experimental approaches to assess bioequivalence (BE) in veterinary species have challenges that are not often encountered with human skin. This is especially the situation with locally acting drugs. The focus of this paper is to address several of the challenges associated with (i) determining the BE of these locally acting drugs and (ii) critically examine the current technological advances that can act as a surrogate for clinical trials.     

Should licking behavior be considered in the bioavailability evaluation of transdermal products?

Antiparasitic drugs, and especially macrocyclic lactones (MLs), are often formulated as pour-on products because of their ease of administration, convenience, and reduction of stress in treated animals. However, because of self- and allo-grooming, much of a drug administered transdermally may be systemically absorbed via the oral route, creating highly variable pharmacokinetic and pharmacodynamic response in treated (and untreated) animals. Testing bioequivalence (BE) of pour-on drugs in cattle under laboratory conditions (with restricted licking) ignores a major factor of drug disposition of these drugs and thus fails to predict therapeutic equivalence in the target population under clinical conditions of use. Therefore, the interanimal and intra-animal variability associated with licking behavior should be considered as a biological fact, rather than a noise that needs to be reduced or eliminated. As a result, it is recommended that the BE testing for pour-on products in cattle be conducted by evaluating both the mean and distribution of bioavailability parameters between the reference and test products when animals are not prevented from allo- and self-licking.     

兽用化学药品血药浓度法生物等效性试验技术指导原则简述

血药浓度法生物等效性试验是兽药生物等效性研究的重要方法。为科学规范兽用化学药品生物等效性研究,保障兽药安全、有效、质量可控,在已发布实施的《兽用化学药品生物等效性试验指导原则》基础上,农业农村部兽药评审中心参考相关最新技术指导原则,结合国内兽药研究现状,修订发布了《兽用化学药品血药浓度法生物等效性试验技术指导原则》。本文针对该指导原则的适用范围、试验设计的内容进行阐述,旨在加强研发单位或相关临床试验机构对此指导原则的理解,对生物等效性试验的有效开展提供指导与帮助。     

Bioavailability and bioinequivalence of drug formulations in small animals.

Differences in bioavailability of many drugs from their various dosage forms have been shown to be relatively common in human medicine. Although comparable bioavailability ('bioequivalence') is though to ensure comparable clinical effectiveness and safety ('therapeutic equivalence'), the relationship between bioinequivalence and therapeutic inequivalence is less clear. Thus the prevalence of clinically important differences in bioavailability is unknown. While similar concerns have arisen about drug products used in small animal practice, there have been few investigations and some earlier reports are incomplete. However, there are indications of bioinequivalence with enteral formulations of ampicillin, aspirin, chloramphenicol, digoxin, mitotane, oxytetracycline, penicillin V and theophylline. Other studies have suggested bioequivalence with enteral formulations of chloramphenicol, digoxin, phenytoin, oxytetracycline and thyroxine. Limited data for injectable preparations showed bioinequivalence with chloramphenicol and possibly oxytetracycline. There is no reason to expect formulation-related bioinequivalence to be less prevalent in veterinary than in human medicine. Indeed, it may be more common in veterinary practice because other potential influences on bioavailability (food, diseases, other drugs, etc.) are frequently ignored, and cheaper generic products are often favoured for economic reasons.     

Challenges associated with the demonstration of bioequivalence of intramammary products in ruminants

This article explores the numerous challenges encountered when the goal is to demonstrate bioequivalence (BE) between test and reference intramammary (IMM) products in ruminants. Numerous pathophysiological factors of mastitis and physicochemical properties of IMM formulations are implicated in the difficulties in confirming BE for this dosage form. Advantages and disadvantages of current BE study designs are discussed, and alternative perspectives are outlined. Ongoing and future research increasing our knowledge of the pharmacokinetics and pharmacodynamics of antimicrobial drugs delivered through this route is crucial to better understanding the implications of clinically significant formulation differences in the demonstration of BE and may also help in developing more effective IMM formulations for ruminants.     

A literature review of reports of the stability and storage of common injectable chemotherapy agents used in veterinary patients

Many chemotherapy drugs used in human patients are discarded after single use or within 24 h of reconstitution, as per the manufacturer's product label recommendations. This can be wasteful and costly to veterinary clients. This report reviews the published stability and storage data for 19 injectable chemotherapy drugs commonly used in veterinary medicine. Based on these data, storage procedures are presented, assuming aseptic technique and a closed system drug transfer device (CSDTD) are used for drug preparation and handling. Further studies on the risk of microbiological contamination of chemotherapeutics using a CSDTD, and validated high quality drug assays such as stability‐indicating high‐performance liquid chromatography, are required. The authors' intent is not to supersede product label recommendations, but to suggest that longer storage without significant loss of drug efficacy may be possible, thus reducing the costs of chemotherapeutics to some veterinary clients.     

Enantioselective behaviour of drugs used in domestic animals: a review

The chirality of drugs, with particular reference to agents used in veterinary medicine, is reviewed. Basic concepts of chirality and aspects of the methodology for the separation of enantiomers are considered. Chiral compounds are in common use in animals and their pharmacological actions and side-effects (pharmacodynamics) and absorption into and fate within the body (pharmacokinetics) are of fundamental importance; pharmacodynamic and pharmacokinetic properties of enantiomeric pairs commonly differ and this has major implications for their effective and safe therapeutic use. As examples of the particular significance of chirality in veterinary medicine, the following drug classes are reviewed; benzimidazole anthelmintics, cloprostenol, verapamil, ketamine, halogenated hydrocarbon anaesthetics and 2-arylpropionic acid anti-inflammatory drugs. The implications of chirality for drug product development and approval by registration authorities are discussed.     

山东省减抗背景下的中兽药产业调研分析

基于对山东省兽药生产企业和养殖企业中兽药生产和使用情况的调研,本文深入分析了我省中兽药发展现状和存在的问题,针对性地提出了中兽药产业发展的对策建议。需着力构建全产业链发展格局;不断释放市场创新创业活力;快速实现我省中兽药产业现代化;充分发挥好政策对产业引领作用;着力打造专业化人才队伍。并不断推进兽用抗菌药减量化示范行动等综合措施,从根本上遏制兽用抗菌药滥用,提倡使用中兽药等绿色高效产品的减抗行动,以期降低细菌耐药性的发生和发展,保障畜禽产品质量安全。     

Pharmaco-epidemiology and -economics should be developed more extensively in veterinary medicine

Pharmaco-epidemiology, which has emerged within the last 20 years as a new discipline in human medicine, deals with the quantities of drugs consumed and their effects on populations in terms of epidemiological concepts and tools. To a lesser extent, it is also practised in veterinary medicine. The applications presented in this review are illustrative of pharmaco-epidemiological and -economical concepts. Assessment of drug consumption, the study of adverse drug effects, and the economic implications of drug use are the three main fields considered. Developments can be expected in veterinary medicine within the next few years relative to novel areas of interest such as antimicrobial resistance and new therapeutic class uses. These applications will require methodological progress and the elimination of current gaps. Pharmaco-epidemiological methods need to be developed, which implies close co-operation between statisticians, pharmacologists, veterinary practitioners and epidemiologists. A greater use of the term 'pharmaco-epidemiology' as a keyword in literature would facilitate recognition of this domain which associates closely epidemiology and pharmacology.     

Canine ABCB1 and macrocyclic lactones: heartworm prevention and pharmacogenetics

The impact of drug transporters on drug pharmacokinetics and pharmacodynamics has been increasingly recognized in recent years. P-glycoprotein (P-gp), the product of the ABCB1 (formerly MDR1) gene, is among the most well-characterized drug transporters, particularly in veterinary medicine. P-gp is expressed by a variety of normal tissues, including the intestines, brain capillary endothelial cells, renal tubular cells, and biliary canalicular cells, where it functions to actively extrude substrate drugs. In this capacity, P-gp limits oral absorption and central nervous system entry of many substrate drugs and enhances their excretion from the body. Many drugs used in veterinary medicine are substrates for P-gp, including many chemotherapeutic agents and macrocyclic lactones (avermectins and milbemycin). A 4-base pair deletion mutation in the ABCB1 gene occurs in many herding breed dogs, including collies, Australian shepherds, and Shetland sheepdogs. The mutation (ABCB1-1Delta) renders affected animals extremely susceptible to toxicosis induced by substrate drugs, such as the macrocyclic lactones at doses well below those tolerated by dogs with the wild-type ABCB1 gene. However, at the manufacturer's recommended dose, all FDA-approved heartworm preventive products marketed in the United States are safe, even for dogs with the ABCB1 mutant/mutant genotype.     

宁夏市场兽药质量检测结果分析

为了解与分析宁夏2016～2019年兽药产品抽检中不合格产品概况,以利于有目的有重点地对兽药产品的质量进行有效监督,根据宁夏兽药饲料监察所2016～2019年抽检兽药产品的统计数据,对抽检项目、剂型、类别及来源等进行统计分析。结果表明,四年共抽检产品1265批次,其中合格1165批,不合格100批,合格率为92.09%。不合格项目主要为含量测定;不合格产品以中药类最多;不合格剂型,以散剂为主;不合格产品多来自经营环节。应加强兽药产品的监督与指导,保证广大养殖户用药安全有效以及保障畜产品质量安全。     

胶体金免疫层析技术在动物病毒性传染病诊断中的应用

自胶体金标记技术问世以来,已在妊娠检测、传染病、毒品、食品安全和兽医等领域得到了广泛的应用.就兽医领域而言,已应用在动物寄生虫、细菌、病毒以及兽药残留检测等方面.论文总结了胶体金免疫层析技术的基本原理和常见的检测抗原、抗体的方法,对胶体金免疫层析技术在动物病毒抗原和抗体检测中的应用进行了详细的介绍,并对该技术在动物病毒...     

Connecting knowledge resources to the veterinary electronic health record: opportunities for learning at point of care

Electronic health records (EHRs) provide clinical learning opportunities through quick and contextual linkage of patient signalment, symptom, and diagnosis data with knowledge resources covering tests, drugs, conditions, procedures, and client instructions. This paper introduces the EHR standards for linkage and the partners-practitioners, content publishers, and software developers-necessary to leverage this possibility in veterinary medicine. The efforts of the American Animal Hospital Association (AAHA) Electronic Health Records Task Force to partner with veterinary practice management systems to improve the use of controlled vocabulary is a first step in the development of standards for sharing knowledge at the point of care. The Veterinary Medical Libraries Section (VMLS) of the Medical Library Association's Task Force on Connecting the Veterinary Health Record to Information Resources compiled a list of resources of potential use at point of care. Resource details were drawn from product Web sites and organized by a metric used to evaluate medical point-of-care resources. Additional information was gathered from questions sent by e-mail and follow-up interviews with two practitioners, a hospital network, two software developers, and three publishers. Veterinarians with electronic records use a variety of information resources that are not linked to their software. Systems lack the infrastructure to use the Infobutton standard that has been gaining popularity in human EHRs. While some veterinary knowledge resources are digital, publisher sites and responses do not indicate a Web-based linkage of veterinary resources with EHRs. In order to facilitate lifelong learning and evidence-based practice, veterinarians and educators of future practitioners must demonstrate to veterinary practice software developers and publishers a clinically-based need to connect knowledge resources to veterinary EHRs.     

兽用中药配方颗粒研究进展

近年来,中兽药在现代畜禽养殖、对抗动物疫病、调节改善动物免疫力方面都发挥了重要的作用,但是其在畜禽给药途径和生物利用度方面还存在一定不足。畜禽消化系统的不同导致给药方式必然存在不同,兽用中药配方颗粒使用方便,而且生物利用度高于中药散剂。目前尚无兽用中药配方颗粒的相关研究,本文对兽用中药配方颗粒的研究进展进行归纳总结,以期为兽用中药配方颗粒的开发利用提供依据。     

中国与美国、欧盟、日本和CAC猪组织中兽药残留限量标准的对比研究

为便于中国兽药残留标准的改进和相关法规体系的建立提供参考,同时为中国畜产品贸易提供数据参考,保障人们的饮食安全,促进中国畜产品经济的更好发展,本研究首先对中国新国标GB 31650-2019《食品安全国家标准食品中兽药最大残留限量》中规定的猪组织中兽药残留种类和兽药最大残留限量（MRLs）标准进行了简单分析;然后对美国、欧盟、日本和食品法典委员会（CAC）规定的猪组织中兽药残留种类和兽药MRLs标准与中国新国标进行对比,通过对规定兽药总数、中国没有规定而其他标准有规定的兽药种类、其他标准严于中国标准的兽药种类等几项内容的比较,找出差异。结果显示,中国新国标做出了更加详细的补充和修改;从整体上来看,中国规定的猪组织中兽药MRLs标准越来越完善,大部分标准与欧盟、美国、日本和CAC规定标准的差距也越来越小,然而在部分种类兽药MRLs标准的规定方面和这些国家或组织仍有一定的差距。中国需加强与各个发达国家和组织的交流与合作,推进中国的兽药残留标准的发展,加快对动物产品质量安全标准的更新。     

中美兽药产业内贸易研究

文章根据2000-2017年中美兽药产品贸易的进口额和出口额，计算了中美两国兽药产品产业内贸易G-L指数及B指数，分析两国兽药产业内贸易情况。经研究认为，中美兽药产业内贸易整体水平不高，但是呈近年来上升趋势，且中美兽药贸易增加的原因以产业内贸易为主。另外，中美兽药产业的产业内贸易可能是受到市场需求差异、产品差异、规模经济等因素的影响。最后，针对研究结果提出促进中美产业内贸易发展的建议,包括继续充分利用两国资源禀赋的互补性，加大技术引进、技术创新的力度，加强中美兽药产业贸易更进一步向产业内贸易的转化。