Population variability in animal health: Influence on dose‐exposure‐response relationships: Part II: Modelling and simulation

During the 2017 Biennial meeting, the American Academy of Veterinary Pharmacology and Therapeutics hosted a 1‐day session on the influence of population variability on dose‐exposure‐response relationships. In Part I, we highlighted some of the sources of population variability. Part II provides a summary of discussions on modelling and simulation tools that utilize existing pharmacokinetic data, can integrate drug physicochemical characteristics with species physiological characteristics and dosing information or that combine observed with predicted and in vitro information to explore and describe sources of variability that may influence the safe and effective use of veterinary pharmaceuticals.     

Multiple comparison procedure and modeling: a versatile tool for evaluating dose–response relationships in veterinary pharmacology – a case study with furosemide

Congestive heart failure (CHF) is a leading cause of mortality with an increasing prevalence in human and canine populations. While furosemide is a loop diuretic prescribed for the majority of CHF patients to reduce fluid retention, it also activates the renin–angiotensin aldosterone system (RAAS) which further contributes to the accelerated progression of heart failure. Our objective was to quantify the effect of furosemide on diuresis, renin activity (RA), and aldosterone (AL) in dogs, using a combined multiple comparisons and model‐based approach (MCP‐Mod). Twenty‐four healthy beagle dogs were allocated to four treatment groups (saline vs. furosemide 1, 2, and 4 mg/kg i.m., q12 h for 5 days). Data from RA and AL values at furosemide trough concentrations, as well as 24‐h Diuresis, were analyzed using the MCP‐Mod procedure. A combination of E_max models adequately described the dose–response relationships of furosemide for the various endpoints. The dose–response curves of RA and AL were found to be well in agreement, with an apparent shallower slope compared with 24‐h Diuresis. The research presented herein constitutes the first application of MCP‐Mod in Veterinary Medicine. Our data show that furosemide produces a submaximal effect on diuresis at doses lower than those identified to activate the circulating RAAS.     

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.     

Anti‐diabetic effect of camel milk in alloxan‐induced diabetic dogs: a dose–response experiment

This study was conducted to evaluate the effect of camel milk in alloxan‐induced diabetic dogs and to follow this effect at three doses of milk. Firstly, three groups of dogs were used: two groups composed each of four diabetic dogs and receiving raw camel milk (treatment 1) or cow milk (treatment 2), and four healthy dogs getting raw camel milk (treatment 3) were used as control. Each animal was treated with 500 ml of milk daily. Secondly, we compared the effects of three amounts of camel milk: 100 ml, 250 ml and 500 ml to treat the diabetic dogs. After week 3, the dogs treated with camel milk showed a statistically significant decrease in blood glucose (from 10.88 ± 0.55 to 6.22 ± 0.5 mmol/l) and total protein concentrations (from 78.16 ± 2.61 g/l to 63.63 ± 4.43 g/l). For cholesterol levels, there was a decrease from week 2 (from 6.17 ± 0.5 mmol/l to 4.79 ± 0.5 mmol/l). There were no significant difference in blood glucose, cholesterol or total protein concentrations in dogs drinking 250 and 500 ml of camel milk. The dogs treated with 100 ml of camel milk did not show any significant decrease in blood glucose levels, and cholesterol and total protein concentrations. The investigation was not limited to the improvement in glycemic balance, lipids and proteins control in diabetic dogs getting camel milk, but we also noted a stability of this state after the dogs stopped to drink milk. This effect depended on the quantity of camel milk used to treat diabetic dogs.     

Occupational health and safety in small animal veterinary practice: Part I--nonparasitic zoonotic diseases

Zoonotic diseases are an ever-present concern in small animal veterinary practice and are often overlooked. A variety of nonparasitic zoonotic diseases may be encountered in small animal practice, including cat scratch disease (bartonellosis), cat bite abscesses, rabies, leptospirosis, methicillin-resistant Staphylococcus aureus, Clostridium difficile-associated diarrhea, salmonellosis, avian chlamydiosis, campylobacteriosis, dermatophytosis, and blastomycosis. These may cause human disease ranging from mild and self-limiting to fatal. The risk of development of a zoonotic disease can be lessened by early recognition of infected animals, proper animal handling, basic biosecurity precautions, and, most importantly, personal hygiene.     

Gastroprotectants in small animal veterinary practice – a review of the evidence. Part 1: cyto‐protective drugs

Diverse drugs with presumed cytoprotective effect have been used therapeutically in small animal veterinary practice for various gastro‐intestinal conditions such as oesophagitis, gastric ulceration, gastritis or chronic gastro‐enteropathies. Their efficacy has been doubted in human medicine, raising similar questions in the veterinary field. The aim of this review was to assess the current evidence on the efficacy and safety of these drugs in dogs and cats. Through a systematic review of the literature, we identified 37 articles on the use of misoprostol, sucralfate and other gastroprotectants in dogs and cats. There was evidence to support use of misoprostol in the prevention of aspirin‐induced gastroduodenal mucosal injury in dogs, and for use of sucralfate in the prevention of acid‐induced oesophagitis in cats. However, the overall quality of evidence supporting the use of these drugs in small animal patients was poor. In contrast, there was evidence of important adverse effects, especially drug interaction and gastro‐intestinal signs. We therefore recommend prescribing these drugs with caution until further well‐conducted studies reveal a useful gastroprotectant effect.     

Mathematical modeling and simulation in animal health – Part II: principles,methods, applications,and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment

This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food‐producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food‐producing animals. The advantages and disadvantages of PBPK modeling compared to other pharmacokinetic modeling approaches (i.e., classical compartmental/noncompartmental modeling, nonlinear mixed‐effects modeling, and interspecies allometric scaling) are further presented. The review finally discusses contemporary challenges and our perspectives on model documentation, evaluation criteria, quality improvement, and offers solutions to increase model acceptance and applications in veterinary pharmacology and toxicology.     

Postpartum reproductive performance in dairy cows. I: Influence of animal, breed and parity

The purpose of this study was to evaluate the influence of animal, breed and parity on postpartum reproductive functions in dairy cows. A total of 141 cows were included in the experiment, which was carried out as part of a study on traits affecting longevity in Swedish dairy cows. The cows belonged to 4 different breed-groups and were 1st to 5th calvers. The duration of the study was 3 years and 44 cows were followed during 1 postpartum period, 49 cows during 2 consecutive periods, 43 cows during 3 periods and 5 cows during 4 periods.The cows were clinically examined, by rectal palpation, at 10-day intervals between calving and first AI, which was at first normal oestrus more than 50 days after calving. External signs of heat were checker and recorded three times daily by the herdsmen. Blood samples for progesterone assay were taken at days 10, 15 and 20 after calving and thereafter every 10th day until first AI. Samples taken at days 10, 15 and 20 were also assayed for content of 15-keto-13,14-dihydro-PGF_2α.Heat detection records, records from clinical examinations and plasma progesterone assays were chronologically compiled for each postpartum period and based on this, intervals between calving and postpartum ovulations, recorded uterine involution, 1st and subsequent oestrus and regular reproductive functions were estimated. Least-squares methods were used for the statistical evaluation of data.The results indicate a large variation within and between cows in postpartum reproductive performance. In the total material 1st ovulation occurred before recorded uterine involution and there was a close relationship between 1st ovulatory oestrus and the onset of regular reproductive functions. The interval between calving and 1st ovulation significantly influenced the length of the first cycle in the sense that a large proportion of the early ovulating cows had a short interval between 1st and 2nd postpartum ovulations. The large variations were also evident in the plasma levels of 15-keto-13,14-dihydro-PGF_2α. There was a marked decline between days 10 and 15 postpartum and most cows were close to basal levels at 20 days postpartum.The individual cow had a significant influence on intervals from calving to recorded uterine involution, 1st ovulatory oestrus, regular reproductive functions and conception. The breed influence was significant for intervals between calving and 1st ovulation and recorded uterine involution whereas the parity of the cow only influenced the interval between calving and recorded uterine involution.     

Safety evaluation of combination CCNU and continuous toceranib phosphate (Palladia®) in tumour‐bearing dogs: a phase I dose‐finding study

While maintaining a standard toceranib dosage [2.75 mg kg^?1, PO, every other day (EOD)], three dose‐escalating CCNU cohorts up to and including 60 mg m^?2, PO, q3wk, were completed. The dose‐limiting toxicities (DLT) for the combination were neutropenia and the maximum tolerated dose (MTD) for CCNU when given with continuous toceranib was determined to be 50 mg m^?2, q3wk. While activity is not a primary objective of phase I trials, we observed one complete (lymphoma) and four partial responses (lymphoma, sarcoma, undifferentiated carcinoma and prostatic carcinoma) and two dogs experienced stable disease for >6 weeks [gastric adenocarcinoma and metastatic multilobulated osteochondrosarcoma (MLO)] for an objective response rate of 38.4% and a biological response rate of 53.8%. Concurrent continuous toceranib (2.75 mg kg^?1, EOD) and pulse dose CCNU (50 mg m^?2, q3wk) was well tolerated. Phase II effectiveness and phase III prospective randomized trials should further interrogate the potential activity of this combination.     

Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose‐finding study

Combination chemotherapy holds promise for improving outcomes in malignancy when compared with single‐agent approaches. Care must be taken to avoid overlapping toxicity and to utilize agents with differing mechanisms of action. A phase I dose‐finding trial was performed to determine the maximally tolerated dose (MTD) of a concurrent toceranib and doxorubicin (DOX) combination protocol where toceranib dose was maintained at or near 2.75 mg kg^?1 by mouth every other day (PO EOD) while escalating DOX dosage. The dose‐limiting toxicity was found to be neutropenia and the MTD of the combination was determined to be 25 mg m^?2 of DOX q 21 days given concurrently with toceranib 2.75 mg kg^?1 PO EOD. This combination was well tolerated with no excessive gastrointestinal toxicity nor novel adverse events (AEs) noted. Anti‐tumour activity was observed in the majority of cases. This combination warrants further investigation in the context of phase II/III clinical trials to characterize efficacy and long‐term AE profiles.     

Cloning of farm animals: impact on animal health and welfare and implications in trade

The commercial use of animal cloning for breeding food producing animals has been limited so far by biological and technical constraints such as adverse effects on the health and welfare of animals, especially high perinatal and postnatal disease and mortality of clones. However, the improvement of the technique may overcome those problems in future and contribute to the spread of cloning in agricultural production, which raises concern not only on health and welfare aspects but also on food safety and ethics. This may cause conflict in international trade. The present article reviews these topics on the basis of up-to-date scientific opinions.     

ASAS-NANP SYMPOSIUM: Review of systems thinking concepts and their potential value in animal science research

Worldwide, our collective research and policy institutions, including the American Society of Animal Science (ASAS), are calling for more systems-based research and analysis of society’s most pressing and complex problems. However, the use of systems analysis within animal science remains limited and researchers may not have the tools to answer this call. This review thus introduces important concepts in systems thinking methodology, such as policy resistance, feedback processes, and dynamic complexity. An overall rationale for systems thinking and analysis is presented, along with examples of the application of these concepts in current animal science research. In order to contrast systems approaches to more frequently employed event-oriented research frameworks, both frameworks are then applied to the ASAS’ identified “Grand Challenge” problem of antimicrobial resistance (AMR) in order to compare these two kinds of analyses. Systems thinking stresses the importance of underlying system structures that lead to persistent problem behaviors vs a focus on unidirectional cause-and-effect relationships. A potential systems framework for animal production decisions to use antimicrobials is shown that more explicitly accounts for AMR in a way that can lead to different animal production decisions than the event-oriented framework. Acknowledging and accounting for fundamental system structures that can explain persistent AMR will lead to different potential solutions to this problem than would be suggested from more linear approaches. The challenges and benefits of incorporating systems methods into animal science research are then discussed.     

Influence of floor surface and access to pasture on claw health in dairy cows kept in cubicle housing systems

In this study, the effects on the claw health of dairy cows of three different floor types and access to pasture were investigated on 35 farms. The farms were fitted with a given floor type in the indoor walking area of a cubicle housing system: a solid rubber, mastic asphalt or slatted concrete floor. Because we chose farms on which the given floor type was in good condition, the data presented show what can be achieved on these types of floors under ideal circumstances. Cows on half of the farms per floor type had access to pasture during the grazing period. Each farm was visited three times at approx. 6-month intervals at the end of the winter indoor-housing period and at the end of the summer period, i.e. after the period with access to pasture on half of the farms. During each visit, the claw health of the same 10 cows per farm was assessed on the occasion of routine claw trimming. The proportion of cows with haemorrhages increased from mastic asphalt to rubber and slatted concrete floors. A lower proportion of cows kept on mastic asphalt was affected by white-line fissures and needed intermittent claw-trimming, an indicator for lameness. Cows housed in cubicle systems with slatted concrete floors were at the lowest risk of having heel-horn erosions. Access to pasture was associated with a lower incidence of slight white-line fissures and dermatitis digitalis. A higher proportion of cows with sole haemorrhages and sole ulcers were found on all floor types at the end of the summer period than at the end of the winter indoor-housing period. Floor type did not influence the presence of sole ulcers and deep white-line fissures. In conclusion, the effect of floor type on claw health was slight, and none of the investigated floor types was clearly superior to the others. Access to pasture was not effective in reducing the presence of most types of claw lesions associated with the floor type used in the indoor walking area.     

Influence of sickness condition on diurnal rhythms of heart rate and heart rate variability in cows

Parameters of heart rate variability would explain changes in heart rate during the disease status in cows and to evaluate whether such changes might provide a more sensitive and quantitative indicator of these conditions than crude indices. For this purpose, we recorded electrocardiograms for 24 hr using a Holter-type electrocardiograph and applied power spectral analysis of heart rate variability in both five clinically healthy and four hospitalized cows. The significant findings of the current investigation were that the diurnal variations of autonomic nervous function are abolished in cows that are sick. This abnormal rhythm was induced by predominant parasympathetic inhibition in these cows. Therefore, the heart rate variability may be a useful indicator of sickness condition in cows.