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.     

Veterinary drug bioequivalence determination

A bioequivalence trial is a statistically based comparison of two formulations to demonstrate with a controlled consumer (patient) risk that two formulated drug products are interchangeable. The basic assumption underlying a bioequivalence trial is that essentially the same plasma time-course leads to essentially the same effect allowing two formulations to be interchanged. Bioequivalence is generally assessed using kinetic end points and in practice, two formulations in which bioavailability parameters (rate and extent) differ by 20% or less, with a 90% degree of confidence, are considered to be bioequivalent. In this review, the design and evaluation of bioequivalence studies are presented with special attention given to scientific issues.     

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.     

VICH血药法生物等效性指导原则概述

血药法生物等效性试验是开展兽药比对试验工作的重要手段之一。VICH血药法生物等效性指导原则介绍了除多次采血困难的靶动物(如蜂、鱼)的动物血药法生物等效性的实验建议,使基本药代动力学试验、生物等效性试验设计和统计分析原则等在VICH地区得到互认。该指导原则2016年8月开始实施。     

Ivermectin缓控释制剂的研究进展

近年来 ,ivermectin(伊维菌素 ,IVM)缓、控释制剂广泛应用于动物寄生虫及多种疫病的防治 ,本文就其作用、制剂、优点、药物代谢动力学和可能带来的问题等方面进行了综述     

Clinical Trials in Veterinary Medicine: A New Era Brings New Challenges

Randomized clinical trials (RCTs) are among the most rigorous ways to determine the causal relationship between an intervention and important clinical outcome. Their use in veterinary medicine has become increasingly common, and as is often the case, with progress comes new challenges. Randomized clinical trials yield important answers, but results from these studies can be unhelpful or even misleading unless the study design and reporting are carried out with care. Herein, we offer some perspective on several emerging challenges associated with RCTs, including use of composite endpoints, the reporting of different forms of risk, analysis in the presence of missing data, and issues of reporting and safety assessment. These topics are explored in the context of previously reported veterinary internal medicine studies as well as through illustrative examples with hypothetical data sets. Moreover, many insights germane to RCTs in veterinary internal medicine can be drawn from the wealth of experience with RCTs in the human medical field. A better understanding of the issues presented here can help improve the design, interpretation, and reporting of veterinary RCTs.     

Considerations for extrapolating in vivo bioequivalence data across species and routes

The purpose of this article is to discuss the numerous species-specific and route-specific factors that can influence the peak and extent of exposure of an active pharmaceutical ingredient as they relate to the demonstration of bioequivalence between veterinary drug products (test and reference formulations). Evaluation of potential circumstances when species-to-species or route-to-route extrapolations of bioequivalence data could be considered is provided, together with suggestions for alternative statistical analysis. It is concluded that further research is much needed in this area to establish an appropriate scientific basis for across-species and across-route comparisons.     

包衣技术提高药物药学性能的研究进展

兽药对畜牧生产中的疾病防控和健康养殖意义重大,但由于某些药物味苦、对胃黏膜刺激性大、稳定性差和药理作用部位靶向性差等限制了其在临床上的使用。包衣技术在改善药物适口性、提高药物稳定性和实现药物控缓释和靶向性等方面具有显著优势。作者总结了国内外关于包衣技术在改善药物适口性、提高药物稳定性、制备控缓释剂型和高效靶向释药剂型方面的研究进展,分析了包衣膜的形成原理,剖析了几种常见包衣技术的优缺点和其产业化面临的挑战,在此基础上展望了包衣技术在兽药领域的应用前景,以期为基于包衣技术的兽药新制剂的开发提供新思路。     

Recent advances in soft tissue minimally invasive surgery

Advancements in soft tissue minimally invasive surgery have been rapid and comprehensive since its inception in human medicine approximately 25 years ago. From its origins in traditional laparoscopy, followed rapidly by video‐assisted thoracoscopic surgery, minimally invasive surgery in human medicine has evolved through a number of different platforms that now include single‐port approach devices, robotic surgery as well as natural orifice transluminal endosurgery. Whilst some of these remain beyond the reach of veterinary medicine for now, largely because of technical challenges and the prohibitive costs of some single‐use disposable components, veterinary minimally invasive surgery is advancing rapidly allowing our small animal patients to benefit from some of the many documented advantages that a minimally invasive approach affords the patient .     

Bioequivalence of four preparations of enrofloxacin in poultry

In various parts of the world, many 10% enrofloxacin commercial preparations for water medication of chicken are being employed. To avoid the development of bacterial resistance to this agent, the original trademark and similar preparations must be bioequivalent. To assess whether or not bioequivalence exists among the pioneer vs. three commercial preparations of enrofloxacin, a controlled pharmacokinetic study was conducted. The following variables were compared: maximal plasma concentration (Cpeak), time to Cpeak, bioavailability (expressed as the area under the concentration vs. time curve), elimination half-life, and the shapes of the respective time-serum concentrations of enrofloxacin profiles. Results indicate that all three similar commercial preparations had lower Cpeak values than the reference formulation, being 39.62 to 67.77% of the corresponding Cpeak reference. Additionally, bioavailability of enrofloxacin in the pioneer product was statistically higher (P < 0.05). Based upon these results, we conclude that although all preparations were formulated as water-soluble products, bioequivalence studies are mandatory for the analogue formulations to ensure product comparability. Lack of product bioequivalence could facilitate the development of bacterial resistance and limit the useful life span of the product.     

International regulatory considerations pertaining to the development of stem cell-based veterinary medicinal products

Stem cell-based products (SCPs) are an emerging field of veterinary medicine that focuses on the regeneration, repair, or replacement of damaged tissues or organs. However, there are some issues in applying the traditional regulatory guideline for the approval of SCPs as veterinary medicinal products. This article describes the positions of Korea, US, and EU regarding SCPs, and compares the regulatory guidelines of each country for their safety evaluation. Although there are some differences in the regulatory guidelines, similar considerations in identifying the quality of SCPs and their safety has adopted. Overall, these guidelines need to be harmonized among countries.     

Antibiotic resistance--an evolving problem

In 1998, an influential report on antimicrobial resistance from the House of Lords Select Committee on Science and Technology highlighted the threat posed to public health by resistance, and called for products to be used more prudently in both human and veterinary medicine. Here, Lord Soulsby, who chaired the Lords' committee on antimicrobials, and Richard Wise, who advised the committee and is now chairman of the Government's Specialist Advisory Committee on Antimicrobial Resistance, consider what has been achieved since then, along with the challenges that remain.     

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。     

Challenges of Cardiopulmonary Bypass—A Review of the Veterinary Literature

Cardiopulmonary bypass (CPB) has been used in veterinary medicine in experimental surgery and to address congenital and acquired diseases. We review the veterinary literature and expose common challenges of CPB in dogs and cats. Specifically, we describe the most specific elements of this technique in veterinary patients. The variety in animal size has made it difficult to standardize cannulation techniques, oxygenators, and priming volumes and solutions. The fact that one of the most common cardiovascular disorders, mitral valve disease, occurs predominantly in small dogs has limited the use of bypass in these patients because of the need for small, low prime oxygenators and pumps that have been unavailable until recently. Coagulation, hemostasis, and blood product availability have also represented important factors in the way CPB has developed over the years. The cost and the challenges in operating the bypass machine have represented substantial limitations in its broader use.     

New perspectives in cardiovascular medicine: the calcium channel blocking drugs

Calcium channel blocking drugs reduce the influx of calcium (Ca++) through cell membrane passageways in excitable tissues. This unique pharmacodynamic action represents an important new addition to cardiovascular therapeutics. Clinically available members of this diverse group of compounds are verapamil, nifedipine, and diltiazem. Beneficial responses to these drugs can be explained by vasodilatation and resulting hemodynamic improvement in tissue perfusion-oxygen demand relationships, by suppression of Ca++-dependent arrhythmogenic mechanisms, by direct reduction of pathologic Ca++ overload in ischemic injured cells, or by a combination of these effects. Calcium channel blockade already has become a therapeutic mainstay in human medicine for management of ischemic heart disease and some forms of cardiac dysrhythmias. Relative to veterinary medicine, Ca++ channel blocking drugs may provide a clinical option for controlling supraventricular tachyarrhythmias. Other indications might include obstructive cardiomyopathies, shock-trauma, and congestive heart failure. Importantly, however, essential issues about adverse cardiovascular side effects of Ca++ channel blocking drugs remain unresolved and controversial. Recent studies especially have raised questions about the tendency for Ca++ channel blockade to exacerbate preexisting or occult myocardial contractile failure. Such pharmacodynamic complexities should be assessed judiciously as the Ca++ channel blocking drugs are appraised for entry into veterinary internal medicine.     

Food-supply veterinary medicine and veterinary medical education: an Australian perspective

Food-supply veterinary medicine has been an essential part of veterinary degree programs in Australia since the first veterinary school opened in the late nineteenth century. Australian veterinary schools, like others internationally, are being challenged by the relevance of material in current curricula for modern food-supply veterinary medicine. Additionally, student aspirations are a major issue, as curriculum designers balance companion-animal training with the herd/flock-based issues that focus on productivity and profitability. One of the challenges is to examine the relative balance of education in generic skills (self-knowledge, change management, teamwork, leadership, negotiation) with more technically or scientifically based education. An ongoing process of curriculum review and renewal, which involves input from both external and internal stakeholders and allows regular review and assessment, is needed to ensure continuing curriculum relevance.     

The consequences of generic marketing on antibiotic consumption and the spread of microbial resistance: the need for new antibiotics

In both human and veterinary medicine, it has been shown that flooding the market with different generics and/or ‘me‐too’ branded drugs has increased overall antibiotic consumption correlating with the emergence and spread of bacterial resistance to antibiotics. Another possible undesirable consequence of the promotion of generics is the promotion of an economic incentive that encourages the use of old drug products with very poor oral bioavailability, marketed with historical dosage regimens and extensively excreted in the environment. What veterinary medicine rather needs is new innovative and ‘ecofriendly’ antibiotics to actually enforce a more prudent use of antibiotics. For a pharmaceutical company, generics are inexpensive to manufacture and on a short‐term basis, the generic market is very appealing. However, on a long‐term basis, this marketing orientation provides a disincentive to the development of new and innovative products that will be required to meet the therapeutic needs of the veterinary community while being consistent with public health concerns. Indeed, for veterinary medicine, the key issue surrounding antibiotics is public health. It is the opinion of the authors that veterinary antibiotics and/or veterinary drug formulations should be innovative in terms of selectivity (no or minimal impact on the commensal gut flora), biodegradable (with minimal environmental disruption), and more expensive, with a strictly regulated market rather than unselective, cheap, and freely available drugs.