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.     

The dose–response relation for the antinociceptive effect of morphine in a fish,rainbow trout

Jones, S. G., Kamunde, C., Lemke, K., Stevens, E. D. The dose–response relation for the antinociceptive effect of morphine in a fish, rainbow trout. J. vet. Pharmacol. Therap.  35 , 563–570. There have been suggestions that analgesics be used by fish researchers. But in the absence of dose–response data for morphine, this suggestion seems imprudent. The purpose of the present study was to develop a dose–response relationship in fish using six doses of morphine. The response (movement of the fins or tail) to a noxious stimulus (electrical shock to the face region) was monitored before and after a dose of morphine intraperitoneally (i.p.). The i.p. dose of morphine ED₅₀ in rainbow trout was 6.7 ± 0.8 mg/kg (n = 12 at each dose). The plasma morphine concentration EC₅₀ was 4.1 ± 1.5 mg/L. In a second experiment, rainbow trout tested with equal amounts of morphine and naloxone (30 mg/kg) showed that the antinociceptive effect of morphine was blocked by naloxone. It has been suggested that stress‐induced analgesia has been a confounding factor in some fish studies. However, plasma cortisol levels in our study indicated that stress was not a confounding factor in the present experiments. The ED₅₀ for morphine in fish was higher than that reported for humans or other mammals. Our observation showing a dose–response relation for morphine using a noxious stimulus supports arguments for its effectiveness as an antinociceptive drug in 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.     

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.     

Retrospective Study: Trends in plasma transfusion at a veterinary teaching hospital: 308 patients (1996–1998 and 2006–2008)

Objectives – To describe changes in fresh frozen plasma (FFP) utilization over a 10‐year period at a veterinary teaching hospital. To evaluate the effect of FFP administration on specific laboratory parameters. Design – Retrospective observational study. Setting – University teaching hospital. Animals– Two hundred and eighty‐three dogs and 25 cats. Interventions – A hospital database search was performed for all animals receiving FFP during the study periods. Measurements and Main Results – Medical records of patients receiving plasma transfusions from 2006 to 2008 and from 1996 to 1998 were reviewed. Data collected included indications for transfusion, transfused volume, concurrent therapies, clinicopathologic data pre‐ and post‐transfusion, transfusion reactions, days of hospitalization, and outcome. FFP was administered to 112 dogs and 23 cats from 2006 to 2008 and to 171 dogs and 2 cats from 1996 to 1998. Significantly fewer patients received FFP for the treatment of hypoalbuminemia (2006–2008: 15% versus 1996–1998: 53%; P<0.001) or pancreatitis (2006–2008: 2% versus 1996–1998: 13%; P=0.001) and significantly more patients received FFP for coagulopathy (2006–2008: 80% versus 1996–1998: 31%; P<0.001) in the 2006–2008 group compared with the 1996–1998 group. For all patients receiving FFP, there was no difference in mean serum albumin concentration pre‐ and post‐transfusion. Median prothrombin time and activated partial thromboplastin time were significantly decreased post FFP administration. No association was found between the volume of plasma administered and outcome. Conclusions – FFP utilization has changed significantly over a 10‐year period. FFP was used most commonly in 2006–2008 for the correction of coagulopathy. FFP administration was associated with significant reduction in prothrombin time and activated partial thromboplastin time but did not significantly alter albumin concentration when administered at median doses of 15–18 mL/kg.     

Skills and competencies required by veterinary pharmacologists: a blueprint for graduate education in veterinary pharmacology in North America

This report describes the results of two efforts to gather data on the needs of veterinary pharmacology, whether academic or industrial, to better define the skills and competencies that graduate programs in veterinary pharmacology should endeavor to provide. Data collected from an on-line survey of the animal health industry were used to develop a workshop at the biennial meeting of the American Academy of Veterinary Pharmacology and Therapeutics. Lists of skills were developed and categorized, and differences among the skills identified by industry vs. academy were outlined. This report offers a blueprint for graduate education in veterinary pharmacology in terms of the types and details of skills and competencies to better prepare future veterinary pharmacologists.     

Lymphangiosarcoma in 12 dogs: a case series (1998–2013)

Lymphangiosarcoma (LAS) is an uncommon malignant neoplasia arising from lymphatic endothelium; little information exists regarding therapy. Single institutional retrospective review for canine LAS histopathology diagnoses over a 15‐year period yielded 12 dogs. Ten dogs were presented for a mass and/or swelling at cervical, trunk or limb regions. Prior to diagnosis, 10 dogs received empiric wound therapy. Cytology performed in 10 consisted of mild inflammation. Survival ranged from 60, 168 and 876 days for three dogs with palliation; 90 days with prednisone in one; 182 days with chemotherapy in one; 240, 267, 487, 630 and 941 days for five receiving surgery; and 574 days for one receiving surgery, radiation and chemotherapy. One dog is alive with recurrence at 243 days following surgery and carboplatin chemotherapy. Clinical improvement existed in LAS dogs receiving multimodal therapies. Early tissue biopsies are recommended for progressive oedematous lesions of unknown origin.     

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.     

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.     

Risk factors for endoparasitism in dogs: retrospective case–control study of 6578 veterinary teaching hospital cases

Objectives : The diagnostic utility of routine faecal examinations can be greatly enhanced through an appreciation of risk factors most commonly associated with endoparasitism. Methods : From a sample of 6578 canine patients presenting to a veterinary teaching hospital between 1996 and 2006, this study used univariate and multi‐variable techniques to examine putative signalment, medical history and demographic factors predisposing dogs to intestinal parasites. Results : Age and median household income were the strongest predictors of endoparasitism. The odds of a patient being diagnosed with endoparasites were 0·82 times smaller for every 1 year increase in age (OR=0·82, 95% CI: 0·80 to 0·84) and for every $10,000 increase in median household income, the odds were 0·86 times lower (OR=0·86, 95% CI: 0·83 to 0·89). The variables gender, neuter status, month of diagnosis, admitting clinical service and primary diagnosis were not significant predictors. Animals that were presented for underlying medical conditions were less likely to have parasites and the presence of diarrhoea was associated with 76% lower odds of endoparasitism compared to healthy animals (OR=0·76, 95% CI: 0·64 to 0·90). Clinical Significance : Clinicians should maintain a high index of suspicion for parasites in younger patients that live in high population density and low income neighbourhoods.