Patient variation in veterinary medicine--part II--influence of physiological variables

In veterinary medicine, the characterization of a drug's pharmacokinetic properties is generally based upon data that are derived from studies that employ small groups of young healthy animals, often of a single breed. In Part I of the series, we focused on the potential influence of disease processes, stress, pregnancy and lactation on drug pharmacokinetics. In this Part II of the series, we consider other covariates, such as gender, heritable traits, age, body composition, and circadian rhythms. The impact of these factors with respect to predicting the relationship between dose and drug exposure characteristics within an animal population is illustrated through the use of Monte Carlo simulations. Ultimately, an appreciation of these potential influences will improve the prediction of situations when dose adjustments may be appropriate.     

Mathematical modeling and simulation in animal health. Part III: Using nonlinear mixed‐effects to characterize and quantify variability in drug pharmacokinetics

A common feature of human and veterinary pharmacokinetics is the importance of identifying and quantifying the key determinants of between‐patient variability in drug disposition and effects. Some of these attributes are already well known to the field of human pharmacology such as bodyweight, age, or sex, while others are more specific to veterinary medicine, such as species, breed, and social behavior. Identification of these attributes has the potential to allow a better and more tailored use of therapeutic drugs both in companion and food‐producing animals. Nonlinear mixed effects (NLME) have been purposely designed to characterize the sources of variability in drug disposition and response. The NLME approach can be used to explore the impact of population‐associated variables on the relationship between drug administration, systemic exposure, and the levels of drug residues in tissues. The latter, while different from the method used by the US Food and Drug Administration for setting official withdrawal times (WT) can also be beneficial for estimating WT of approved animal drug products when used in an extralabel manner. Finally, NLME can also prove useful to optimize dosing schedules, or to analyze sparse data collected in situations where intensive blood collection is technically challenging, as in small animal species presenting limited blood volume such as poultry and fish.     

The pharmacogenomics of P-glycoprotein and its role in veterinary medicine

Despite advancements in pharmacogenetics in human medicine, the incorporation of pharmacogenetics into veterinary medicine is still in its early stages of development. To date, efforts to understand the pharmacologic impact of genetic variation in veterinary species have largely focused on genes encoding for the membrane transporter, P-glycoprotein (P-gp). The emphasis on the role of P-gp is largely because of safety concerns associated with the use of some macrocyclic lactones in dogs. Because of the body of information available on this topic, we use P-gp as a platform for understanding the importance of population diversity in veterinary medicine. The impact of P-gp on drug pharmacokinetics and pharmacodynamics is considered, along with endogenous and exogenous factors that can modulate P-gp activity. The review includes discussion of how population diversity in P-gp activity can lead to susceptibility to certain diseases or alter patient response to environmental stress or pharmaceutical intervention. In addition, phenotypic diversity also needs to be considered, as demonstrated by the impact of P-gp up-regulation and drug resistance. The aim of this review was to set the stage for further exploration into the impact of genetic and phenotypic variability on drug pharmacokinetics, disease propensity, product formulation and drug response in both companion and food-producing animals.     

Development of a limited‐sampling model for prediction of doxorubicin exposure in dogs

Understanding the relationship between drug dose and exposure (pharmacokinetics, PK) and the relationship between exposure and effect (pharmacodynamics) is an important component of pharmacology when attempting to predict clinical effects of anticancer drugs. PK studies can provide a better understanding of these relationships; however, they often involve intensive sampling over an extended period of time, resulting in increased cost and decreased compliance. Doxorubicin (DOX), one of the most widely used antineoplastic agents in veterinary cancer therapy, is characterized by large interpatient variability in overall drug exposure and the development and degree of myelosuppression following equivalent dosages. We have developed and validated a limited‐sampling strategy for DOX, in which three blood samples are obtained over 1 h post‐treatment, that accurately predicts patient exposure. This strategy could allow for refining of dosing variables and utilization of therapeutic drug monitoring to ensure optimized dosing.     

药动/药效同步模型在兽用抗菌药物研究的应用概况

药动/药效同步模型是将药动学和药效学结合,用于研究药理效应随时间变化规律的一种模型。药动/药效同步模型在药理学和毒理学研究、临床应用及新药评价等领域得到越来越广泛的应用。随着抗菌药物的发展,耐药性问题日益成为全球关注的焦点。将药动/药效同步模型引入兽药研究中,不仅能够优化给药方案,避免细菌耐药性的产生,也能够为新药的开发提供研究基础。论文对兽用抗菌药物的分类、药动/药效同步模型的研究方法及其在国内外兽药研究中的应用现状进行综述,以期为药动/药效同步模型的兽医临床应用提供参考。     

犬品种之间的药物遗传和代谢差异

描述动物物种的相关药理学遗传差异的资料非常有限。尽管在兽医药学的遗传信息缺乏,但品种对内在的和外在的物质的具体反应已经有许多物种的报告。这一发现强调了当前跨越品种获得洞察基因型和表型变异的重要性。本文提供了有关犬品种在生理学,药物反应,药物药代动力学和代谢特性方面的差异的文献总结。了解这些品种差异将改善犬的人口预测（为了犬的药物产品）,当推断从犬到人类的毒理学数据时可能是有价值的。     

Impact of selected individual dog traits on echocardiographic parameters obtained in 1-dimensional (M-mode) and 2-dimensional (2D) imaging

The popularity and availability of echocardiography in veterinary practice for companion animals have substantially increased in recent years. The results obtained during the procedure are compared to reference values established for the general dog population or to standards developed for a specific dog breed. The aim of this study was to determine whether individual dog traits, such as body weight, chest structure, and level of physical activity and performance, affect the reference values for echocardiographic parameters. Published reference values for echocardiographic examination parameters for 32 dog breeds were analyzed and the relationship between individual echocardiographic parameters and body weight, chest structure, and level of physical activity and performance was then statistically analyzed. It was found that echocardiographic parameters are affected by the dog’s weight and physical activity. There was no significant relationship between heart size and chest structure. The great variety of dog breeds means that echocardiographic findings should be individually interpreted rather than establishing reference ranges for each breed in population studies. This will allow for a more accurate interpretation of the results obtained in the echocardiographic examination and consequently lead to earlier diagnosis of changes in myocardial morphology.     

兽药缓控释制剂的研究进展

长效制剂由于其可以减少给药次数同时保证药效等一系列优点在兽药领域发展较快。综述了国内外兽药领域开发研制的多种缓控释制剂,包括缓释装置、新型的缓释剂型等。并对其制备、性能药物释放行为做了详尽的说明,并对兽药缓控释制剂未来的发展做了进一步的展望。     

Population variability in animal health: Influence on dose–exposure–response relationships: Part I: Drug metabolism and transporter systems

There is an increasing effort to understand the many sources of population variability that can influence drug absorption, metabolism, disposition, and clearance in veterinary species. This growing interest reflects the recognition that this diversity can influence dose–exposure–response relationships and can affect the drug residues present in the edible tissues of food‐producing animals. To appreciate the pharmacokinetic diversity that may exist across a population of potential drug product recipients, both endogenous and exogenous variables need to be considered. The American Academy of Veterinary Pharmacology and Therapeutics hosted a 1‐day session during the 2017 Biennial meeting to explore the sources of population variability recognized to impact veterinary medicine. The following review highlights the information shared during that session. In Part I of this workshop report, we consider sources of population variability associated with drug metabolism and membrane transport. Part II of this report highlights the use of modeling and simulation to support an appreciation of the variability in dose–exposure–response relationships.     

Transdermal drug delivery: basic principles for the veterinarian

The use of topical pharmaceutical formulations is increasingly popular in veterinary medicine. A potential concern is that not all formulations are registered for the intended species, yet current knowledge strongly suggests that simple extrapolation of transdermal drug pharmacokinetics and pharmacodynamics between species, including humans, cannot be done. In this review, an overview is provided of the underlying basic principles determining the movement of topically applied molecules into and through the skin. Various factors that may affect transdermal drug penetration between species, between individuals of a particular species and regional differences in an individual are also discussed. A good understanding of the basic principles of transdermal drug delivery is critical to avoid adverse effects or lack of efficacy when applying topical formulations in veterinary medicine.     

Population pharmacokinetics in veterinary medicine: Potential use for therapeutic drug monitoring and prediction of tissue residues

Population pharmacokinetics can be defined as a study of the basic features of drug disposition in a population, accounting for the influence of diverse pathophysiological factors on pharmacokinetics, and explicitly estimating the magnitude of the interindividual and intraindividual variability. It is used to identify subpopulations of individuals that may present with differences in drug kinetics or in kinetic/dynamic responses. Rooted in procedures used in engineering systems, population pharmacokinetics methods were conceived as a means to determine the pharmacokinetic profile in populations in which a sparse number of samples were obtained per individual, such as those in late stage human clinical trials. This is the situation commonly encountered in all aspects of veterinary medicine. The exploratory nature of this technique allows one to probe relationships between clinical factors (such as age, gender, renal function, etc.) and drug disposition and/or effect. Similarly, the utilization of these techniques in the clinical research phases of drug development optimize the determination of efficacy and safety of drugs. Given the observational nature of most studies published so far, statistical methods to validate the population models are necessary. Simulation studies may be conducted to explore data collection designs that maximize information yield with a minimum expenditure of resources. The breadth of this approach has allowed population studies to be more commonly employed in all areas of drug therapy and clinical research. Finally, in veterinary medicine, there is an additional field in which population studies are potentially ideally suited: the application of this methodology to the study of tissue drug depletion and drug residues in production animals, and the establishment of withdrawal times tailored to the clinical or production conditions of populations or individuals. Such application would provide a major step toward assuring a safe food supply under a wide variety of dose and off-label clinical uses. Population pharmacokinetics is an ideal method for generating data in support of the implementation of flexible labelling policies and extralabel drug use recently approved under AMDUCA (Animal Medicinal Drug Use Clarification Act. 21 CFR Part 530).     

Discussion of the Compendium of Veterinary Standard Precautions: preventing zoonotic disease transmission in veterinary personnel

Veterinary practices are unique environments that bring humans into close contact with many different species of animals; therefore, the risk of exposure to infectious pathogens is inherently different in veterinary medicine than in human medicine. In contrast to the risk of exposure to blood in human medicine, infections from zoonotic diseases in veterinary personnel are primarily related to exposure to animal faeces, infected skin, wounds, droplets and puncture wounds. Infection-control measures in veterinary practices are often insufficient to prevent zoonotic disease transmission. The Veterinary Standard Precautions (VSP) Compendium is designed to help prevent transmission of zoonotic pathogens from animal patients to veterinary personnel in private practice.     

Drug hypersensitivity reactions targeting the skin in dogs and cats

Adverse drug reactions (ADRs) can be dose dependent or idiosyncratic. Most idiosyncratic reactions are believed to be immune-mediated; such drug hypersensitivities and allergies are unpredictable. Cutaneous reactions are the most common presentation of drug allergies. In veterinary medicine it can be difficult to assess the true prevalence of adverse drug reactions, although reports available suggest that they occur quite commonly. There are multiple theories that attempt to explain how drug allergies occur, because the pathogenesis is not yet well understood. These include the (pro)-hapten hypothesis, the Danger Theory, the pi concept, and the viral reactivation theory. Cutaneous drug allergies in veterinary medicine can have a variety of clinical manifestations, ranging from pruritus to often fatal toxic epidermal necrolysis. Diagnosis can be challenging, as the reactions are highly pleomorphic and may be mistaken for other dermatologic diseases. One must rely heavily on history and physical examination to rule out other possibilities. Dechallenge of the drug, histopathology, and other diagnostic tests can help to confirm the diagnosis. New diagnostic tools are beginning to be used, such as antibody or cellular testing, and may be used more in the future. There is much yet to learn about drug allergies, which makes future research vitally important. Treatment of drug allergies involves supportive care, and additional treatments, such as immunosuppressive medications, depend on the manifestation of the disease. Of utmost importance is to avoid the use of the incriminating drug in future treatment of the patient, as subsequent reactions can be worse, and ultimately can prove fatal.     

Integration and modelling of pharmacokinetic and pharmacodynamic data to optimize dosage regimens in veterinary medicine

In veterinary drug development procedures, pharmacokinetic (PK) and pharmacodynamic (PD) data have generally been established in separate, parallel studies to assist in the design of dosage schedules for subsequent evaluation in clinical trials. This review introduces the concept of PK/PD modelling, an approach in which PK and PD data are generated in the same study, and used to derive numerical values for PD parameters based on drug plasma concentrations. The PD parameters define the efficacy, potency and slope (sensitivity) of the concentration-effect relationship. It is proposed that the parameters derived from PK/PD modelling may be used as an alternative and preferred approach to dose titration studies for selecting rational dosage regimens (both dose and dosing interval) for further evaluation in clinical trials. In PK/PD modelling, the explicative variable for effect is the plasma concentration profile. The PK/PD approach provides several advantages over dose-titration studies, including determination of a projected dosage regimen by investigation of a single dose, in contrast to dose-ranging studies which by definition require testing of multiple dosage. Implementation of PK/PD modelling in the veterinary drug development process is currently constrained by the limited number of veterinary studies performed to date, and the consequently limited understanding of PK/PD concepts and their absence from regulatory authority guidelines. Nevertheless, PK/PD modelling has major potential for rational dosage regimen determination, as it considers and quantifies the two main sources of interspecies variability (PK and PD). It is therefore applicable to interspecies extrapolation and to multiple species drug development. As well as the currently limited appreciation of PK/PD principles in the veterinary scientific community, a further constraint in implementing PK/PD modelling is the need to validate PK/PD approaches and thereby gain confidence in its value by pharmaceutical companies and regulatory authorities.     

我国兽用中化药类产品生产剂型及关键生产、检验设备需求研究

通过对兽药产品批准文号情况进行统计分析,发现粉剂、散剂、最终灭菌注射剂等九大类生产剂型是目前我国最主要的中化药兽药产品生产剂型。为此,选择其中的粉剂、注射剂、中药提取生产剂型并对其所需关键生产、检验设备进行重点分析研究,以帮助企业选择适合的生产与检验设备以满足兽药GMP要求,同时也为兽医行政主管部门检查人员履行属地管理职责提供必要的参考。     

Clustering of reported cases of leptospirosis among dogs in the United States and Canada

A retrospective study was conducted to determine whether cases of leptospirosis diagnosed among dogs in the United States and Canada were clustered in time, space, or time-and-space. The study population was estimated--based on first examination of each dog--to consist of 1,035,366 dogs examined at 22 veterinary teaching hospitals between 1983 and 1998. The veterinary medicine database was searched for records of dogs in which a diagnosis of leptospirosis was made during the study period. The scan statistic (Poisson model) was used to examine for clustering of cases, using recorded date of diagnosis and the location of the veterinary teaching hospital at which the diagnosis was made. Three-hundred and forty dogs diagnosed with leptospirosis were identified. Cases were clustered in the period of 1992-1998. A cluster of dogs diagnosed at three veterinary teaching hospitals located in the midwest of the United States was identified. The composition of this spatial cluster was influenced by the age and gender distribution of the population at-risk. A cluster of cases involving 143 dogs diagnosed with leptospirosis between 9 April 1993 and 14 December 1998 at six veterinary teaching hospitals located in the midwest of the United States was identified. This time-space cluster was not influenced by the age, gender or breed distribution of the population of dogs presented at veterinary teaching hospitals during the study period. Leptospirosis was clustered during the 1990s in the midwest of the United States. Dog risk factors (age, gender, breed) do not explain the clustering that was observed. Leptospira serovar or environmental factors might be responsible for the clustering of canine leptospirosis in the United States and Canada.     

Estimation of additive and non-additive genetic parameters for reproduction, growth and survival traits in crosses between the Moroccan D'man and Timahdite sheep breeds

Genetic breed differences, heterosis, recombination loss, and heritability for reproduction traits, lamb survival and growth traits to 90 days of age were estimated from crossing D'man and Timahdite Moroccan breeds. The crossbreeding parameters were fitted as covariates in the model of analysis. The REML method was used to estimate (co)variance components using an animal model. The first estimation of crossbreeding effects for Timahdite and D'man breeds shows that breed differences in litter traits are mainly of maternal genetic origin: +1.04 lambs, +1.88 kg, +0.60 lambs, and +2.23 kg in favour of D'man breed for litter size at lambing, litter weight at lambing, litter size at weaning, and litter weight at 90 days, respectively. The breed differences in lamb growth and survival are also of maternal genetic origin for the majority of traits studied, but in favour of the Timahdite breed: +3.48 kg, +45 g day⁻¹ and +0.19 lambs for weight at 90 days, for average daily gain between 30 and 90 days of age, and for lamb survival to 90 days, respectively. The D'man direct genetic effect was low and negative for survival and birth weight of lambs during the first month of life. All traits studied showed positive heterosis effects. Recombination loss effects were not significant. Therefore, crossbreeding of Timahdite with D'man breeds of sheep can result in an improved efficiency of production of saleable lambs. Heritability estimates were medium for litter size but low for the other reproduction traits. Direct heritabilities were low for body weights and lamb survival at 90 days and the corresponding maternal heritabilities showed, however, low to moderate estimates. For litter traits, the estimates of genetic and phenotypic correlations were positive and particularly high for genetic correlations.     

Feline genetics: clinical applications and genetic testing

DNA testing for domestic cat diseases and appearance traits is a rapidly growing asset for veterinary medicine. Approximately 33 genes contain 50 mutations that cause feline health problems or alterations in the cat's appearance. A variety of commercial laboratories can now perform cat genetic diagnostics, allowing both the veterinary clinician and the private owner to obtain DNA test results. DNA is easily obtained from a cat via a buccal swab with a standard cotton bud or cytological brush, allowing DNA samples to be easily sent to any laboratory in the world. The DNA test results identify carriers of the traits, predict the incidence of traits from breeding programs, and influence medical prognoses and treatments. An overall goal of identifying these genetic mutations is the correction of the defect via gene therapies and designer drug therapies. Thus, genetic testing is an effective preventative medicine and a potential ultimate cure. However, genetic diagnostic tests may still be novel for many veterinary practitioners and their application in the clinical setting needs to have the same scrutiny as any other diagnostic procedure. This article will review the genetic tests for the domestic cat, potential sources of error for genetic testing, and the pros and cons of DNA results in veterinary medicine. Highlighted are genetic tests specific to the individual cat, which are a part of the cat's internal genome.