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.     

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.     

Dihydrostreptomycin or streptomycin in combination with penicillin G in dairy cattle therapeutics: A review and re-analysis of published data Part 2: Resistance and residues

Combination formulations of penicillin G salts and dihydrostreptomycin were developed during the 1960s and are currently marketed in New Zealand for parenteral and intramammary use in dairy cattle. In this paper, the second part of a two paper series, the mechanisms by which bacteria develop resistance to each of these drugs independently is reviewed and the impact of this resistance on potential for synergy is discussed. Further, the considerable potential for tissue drug residues with dihydrostreptomycin or streptomycin from these formulations is examined by re-analysis of literature data, demonstrating an urgent need to reassess the place for aminoglycoside-containing formulations in dairy cattle therapeutics.     

Dihydrostreptomycin or streptomycin in combination with penicillin G in dairy cattle therapeutics: a review and re-analysis of published data. Part 2: resistance and residues

Combination formulations of penicillin G salts and dihydrostreptomycin were developed during the 1960s and are currently marketed in New Zealand for parenteral and intramammary use in dairy cattle. In this paper, the second part of a two paper series, the mechanisms by which bacteria develop resistance to each of these drugs independently is reviewed and the impact of this resistance on potential for synergy is discussed. Further, the considerable potential for tissue drug residues with dihydrostreptomycin or streptomycin from these formulations is examined by re-analysis of literature data, demonstrating an urgent need to reassess the place for aminoglycoside-containing formulations in dairy cattle therapeutics.     

A practitioner's guide to understanding equine infectious disease diagnostics in the United Kingdom. Part 1: How to optimise sampling approaches and a guide to agent detection testing methods

Diagnostic testing is routinely performed by the equine clinician when dealing with suspected infectious disease cases and outbreaks. Optimal sample timing, choice and handling are fundamental to attain an accurate diagnosis, and a good understanding of laboratory-based sample analysis techniques, and their validation is necessary for effective diagnostic test result interpretation. This two-part series highlights the importance of interpreting results bearing testing limitations and specific clinical findings in mind, and on these foundations, the treating clinician should always be well placed to deal with equine infectious diseases. Part 1 in this series will provide a treating clinician with an overview of the importance of testing horses in infectious disease outbreaks and how this is achieved. The different laboratory testing options available for agent detection and their methods will also be discussed. Part 2 will summarise serological (antibody) testing techniques, sample processing (including how tests are performed and validated) and result interpretation.     

Trypanosome genetics: populations, phenotypes and diversity

In the last decade, there has been a wide range of studies using a series of molecular markers to investigate the genotypic diversity of some of the important species of African trypanosomes. Here, we review this work and provide an update of our current understanding of the mechanisms that generate this diversity based on population genetic analysis. In parallel with field based studies, our knowledge of the key features of the system of genetic exchange in Trypanosoma brucei, based on laboratory analysis, has reached the point at which this system can be used as a tool to determine the genetic basis of a phenotype. In this context, we have outlined our current knowledge of the basis for phenotypic variation among strains of trypanosomes, and highlight that this is a relatively under researched area, except for work on drug resistance. There is clear evidence for ‘strain’-specific variation in tsetse transmission, a range of virulence/pathogenesis phenotypes and the ability to cross the blood brain barrier. The potential for using genetic analysis to dissect these phenotypes is illustrated by the recent work defining a locus determining organomegaly for T. brucei. When these results are considered in relation to the body of research on the variability of the host response to infection, it is clear that there is a need to integrate the study of host and parasite diversity in relation to understanding infection outcome.     

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).     

Pharmacokinetics of potassium bromide in adult horses

OBJECTIVE: To determine the pharmacokinetics of potassium bromide (KBr) in horses after a single and multiple oral doses. ANIMALS: Twelve adult Standardbred and Thoroughbred mares. PROCEDURE: Horses were randomly assigned into two treatment groups. In Part 1 of the study, horses were given a single oral dose of 120 mg/kg KBr. Part 2 of the study evaluated a loading dose of 120 mg/kg KBr daily by stomach tube for 5 days, followed by 40 mg/kg daily in feed for 7 days. Serum concentrations of bromide were determined by colorimetric spectrophotometry following drug administration to permit determination of concentration versus time curves from which pharmacokinetic parameters could be calculated. Treated horses were monitored twice daily by clinical examination. Serum concentrations of sodium, potassium and chloride ions and partial pressures of venous blood gases were determined. RESULTS: Maximum mean serum bromide concentration following a single dose of KBr (120 mg/kg) was 284 +/- 15 microg/mL and the mean elimination half-life was 75 +/- 14 h. Repeated administration of a loading dose of KBr (120 mg/kg once daily for 5 days) gave a maximum serum bromide concentration of 1098 +/- 105 microg/mL. The administration of lower, maintenance doses of KBr (40 mg/kg once daily) was associated with decreased serum bromide concentrations, which plateaued at approximately 700 microg/mL. Administration of KBr was associated with significant but transient changes in serum potassium and sodium concentrations, and possible changes in base excess and plasma bicarbonate concentrations. High serum concentrations of bromide were associated with an apparent increase in serum chloride concentrations, when measured on an ion specific electrode. CONCLUSIONS AND CLINICAL RELEVANCE: A loading dose of 120 mg/kg daily over 5 days and maintenance doses of approximately 90-100 mg/kg of KBr administered once daily are predicted to result in serum bromide concentrations consistent with therapeutic efficacy for the management of seizures in other species. The clinical efficacy of this agent as an anticonvulsant medication and/or calmative in horses warrants further investigation.     

Use of atropine to reduce mucosal eversion during intestinal resection and anastomosis in the dog

OBJECTIVE: To determine whether atropine altered the degree of mucosal eversion during jejunal resection and anastomosis in the dog. STUDY DESIGN: Part I: Prospective, blinded, randomized, controlled study using a therapeutic dose (0.04 mg/kg systemic) of atropine. Part II: Prospective, unblinded, assigned, controlled study using a pharmacologic (0.04 mg/kg local arterial) dose of atropine. ANIMALS: Part I: Twenty-two young adult female Beagle dogs used during a nonsurvival third-year veterinary student surgical laboratory (small intestinal resection and anastomosis). Part II: Ten young adult female Beagle dogs used immediately after completion of a nonsurvival third-year veterinary student orthopedic surgical laboratory. METHODS: Part I: Dogs were randomly assigned to receive either atropine (0.04 mg/kg), or an equal volume of saline, given intramuscularly (premedication) and again intravenously prior to intestinal resection. Part II: In each dog, atropine (0.04 mg/kg)/saline was alternately given in the proximal/distal jejunum. RESULTS: Part I: There was no clinically or statistically significant difference between systemic atropine and saline solution on the degree of jejunal mucosal eversion after resection. Part II: There was a statistically significant decrease in jejunal mucosal eversion with atropine compared with saline solution when injected into a local jejunal artery. CONCLUSION: Systemic atropine (0.04 mg/kg) does not alter the degree of jejunal mucosal eversion during resection and anastomosis. Jejunal intraarterial atropine (0.04 mg/kg) reduced jejunal mucosal eversion during resection and anastomosis. CLINICAL RELEVANCE: The clinical usefulness and consequences of jejunal arterial atropine administration to reduce mucosal eversion remain to be determined.     

Current controversies in equine antimicrobial therapy

Controversies exist regarding the use, misuse and potential overuse of antimicrobial treatments in foals and adults. When antimicrobials are required for treatment of infectious diseases, veterinarians should follow a logical approach and not simply reach for the newest drug. Targeted, single drug therapy is probably best, and culture and sensitivity testing should be undertaken. The most likely infectious agent, potential drug toxicities, and age‐appropriate dose and route should be considered. The development of an increasing number of different multiple drug resistant pathogens requires that veterinarians use antimicrobial drugs responsibly to protect veterinary patients and the public at large.     

Influence of sedative and anesthetic agents on intradermal skin test reactions in dogs

To determine the effects of 9 sedative/anesthetic drug protocols on intradermal skin testing, an experimental state of type-I hypersensitivity was created. Intradermal skin tests were performed on 6 dogs, using positive and negative controls and a series of tenfold dilutions of Asc-1 allergen prior to drug administration. Approximately 4 hours later, the dogs were given 1 of the following drugs: acepromazine (low dose and high dose); ketamine hydrochloride with diazepam; thiamylal; oxymorphone; halothane; methoxyflurane; or isoflurane. The intradermal skin test then was repeated, and was scored objectively and subjectively. Objective scores were unaffected by any of the drugs. Subjective scores were affected in that acepromazine decreased wheal size and the induration of the intradermal skin test reaction sites.     

Use of Body Surface Area to Calculate Chemotherapeutic Drug Dose in Dogs: II. Limitations Imposed by Pharmacokinetic Factors

Anticancer drug dosages that specify the maximum dose and minimum dosing interval that are tolerated in a population of dogs are commonly recommended. Because the differences between the effective and toxic doses of most cancer chemotherapeutics is slight, it is important to achieve therapeutic concentrations in tumor tissues at the same time that concentrations in nontarget tissues are minimized. In order to determine the dosage regimen that will most likely accomplish these goals, similar drug concentrations must be achieved in all patients dosed according to a specific regimen. Dosing based on body surface area (BSA) is generally used in an effort to normalize drug concentrations. This is because it is well recognized that measures of many physiologic parameters that are responsible for drug disposition, including renal function and energy expenditure, can be normalized by use of BSA. However, there is substantial evidence that drug disposition is not always proportional to BSA. Differences in distribution, metabolism, and excretion pathways may preclude dose extrapolation among species or among individuals within a species based on BSA. Moreover, genetic differences in drug metabolism are well recognized in humans and in laboratory animals, and it is likely that similar differences exist among breeds of dogs. A review of the pharmacokinetic disposition of several cancer chemotherapeutics suggests that studies are needed to determine the most effective method to achieve equivalent anticancer drug concentrations in diverse veterinary patients.     

Responsible antimicrobial use in critically ill adult horses

Due to increasing antimicrobial resistance, pressure on veterinarians is mounting to adhere to responsible use of antimicrobial drugs. Antimicrobials are frequently included in the treatment of systemically ill horses due to the strong likelihood of an infection and the innate difficulties in differentiating systemic inflammation secondary to noninfectious from infectious causes. In light of increasing antimicrobial drug resistance and the potential negative impact of antimicrobials on equine patients, every attempt should be made to identify noninfectious disease, choose first-line antimicrobials and discontinue treatment as soon as possible. In most cases, a short duration of antimicrobial therapy ranging from a single dose (e.g. preoperatively) to 24–72 h might be sufficient with long-term treatment being rarely required. This article aims to provide practical guidelines for antimicrobial drug usage in critically ill adult horses by describing ancillary diagnostic aids that can help establishing whether or not an infection is present, discussing commonly encountered pathogens and their typical antimicrobial drug sensitivity patterns, and providing some guidance how to safely shorten the duration of antimicrobial therapy.     

Partial prostaglandin-mediated mechanism controlling the release of cortisol in plasma after intravenous administration of endotoxins

In a first series of experiments we studied the influence of E. coli endotoxins or lipopolysaccharides (LPS) administered either intravenously (i.v.) or intramammarily (i.mam.) to lactating goats on plasma cortisol and rectal temperature (RT). Differences in the magnitude of the cortisol release and shape of the fever curve were observed. In both models maximal pyrexia and fever index (FI) were comparable.

In a second series of experiments the influence of LPS on the plasma cortisol and RT was studied after i.v. injection of increasing doses of LPS : low (25 ng/kg), moderate (200 ng/kg) and relatively high (500 ng/kg). Although the cortisol response was dose dependent, the effect was not correlated with FI. The administration of flurbiprofen, a non steroidal anti-inflammatory drug (NSAID), resulted in a complete inhibition of fever at all LPS doses and the cortisol release after administration of low doses LPS. This indicates a prostaglandin mediation. With moderate and high doses LPS the cortisol release was only partially inhibited and delayed suggesting a non prostaglandin mediated mechanism.

In a third series of experiments the influence of flurbiprofen on fever and cortisol release was studied after i.mam. LPS administration. The observed increase of plasma cortisol and RT were completely abolished after flurbiprofen treatment.

It is concluded that: 1) the increase of plasma cortisol after LPS administration in lactating goats is not related to hyperthermia per se, 2) the control of fever and cortisol release may, to some extent, differ according to the LPS dose and method of administration, 3) the cortisol release observed after moderate and high doses of LPS is probably controlled by two phenomena. The first being induced by cyclo-oxygenase metabolites, the second by intermediary mediators other than prostaglandins or by LPS itself. 4) Although an eight-fold higher dose of LPS was given i.mam., a cortisol release comparable to the lowest dose of LPS (25 ng/kg) was observed. These differences in cortisol release can be ascribed to 1) a detoxification of LPS at the level of the mammary gland or 2) a slower resorption of LPS from the mammary gland.     

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.     

Pharmacokinetic estimation for therapeutic dosage regimens (PETDR) – a software program designed to determine intravenous drug dosage regimens for veterinary applications

Pharmacokinetic estimation for therapeutic dosage regimens (PETDR) is a soft-ware program used to design individualized intravenous dosage regimens, determine concentration-time profiles, predict serum concentrations at a specific time after intravenous dosing and predict the time after the last dose to achieve a specified concentration of drug. The reference pharmacokinetic parameters may be based on an individual animal's pharmacokinetic disposition of drug or on FARAD (Food Animal Residue Avoidance Databank) mean population kinetic parameters. An individual animal's kinetic parameters may be input for predetermined analysis or the program can calculate these values by input of raw serum concentration-time data. The program allows the user to specify certain parameters of the dosage regimen, then calculates the other parameters (given desired maximum and minimum serum concentrations, dose and interval are calculated; given desired maximum serum concentration and interval, dose is calculated, etc.). Given the kinetic parameters, the dose and dosing interval, the program calculates and plots the serum concentration-time profile of the drug for that animal. The time and the number of doses to reach steady state can be calculated as well as the determination of loading dose. The percentage of the time of a dosing interval at steady state that the serum concentration is above a specific minimum inhibitory concentration (MIC) allows evaluation of efficacy of an antimicrobial regimen. Similarly, the time to reach a specific concentration (e.g. residue tolerance) or the MIC of a drug can be calculated. Legal tissue tolerances can be accessed from FARAD to aid in predicting for what period of time illegal residues will remain in the animal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Medication control: Rules

The simplest medication rule is a “no detectable level” rule. This rule is used in much of Europe and North America. The principal problem with this rule is that it is virtually impossible to give any guidance to horsemen as to when they should cease drug administration. Part of the reason for this is that the analyst can change the rule at will, simply by changing his detection method.A much more equitable rule is one that specifies a blood or urinary tolerance for a drug. When a tolerance is specified, changing the test method is of no significance, and guidelines can be given to horsemen to help them comply with the rule. The National Association of State Racing Chemists' tolerance for phenylbutazone is a classic example of such a rule.Both of these rules have the advantage that the event which defines the violation is objective and independently verfiable. In each case, the drug can be detected or quantitated by an independent analyst. Independent confirmation removes all doubt as to the scientific basis of the regulatory action.Time rules specify times prior to post during which drugs cannot be administered. While such rules read well and are easy to write, they are troublesome to enforce. This is because enforcement of a time rule depends not on a measured blood or urinary drug level, but rather on an analyst's opinion as to when the drug was administered. This opinion will always have a probability of error, which may be greater, for example, than the number of horses that the analyst tests per year. Under these circumstances, the horsemen's testimony may be correct, and the analyst's opinion incorrect, in a significant proportion of cases. No objective, independent check of the analyst's opinion is possible, and neither are contrary opinions independently verifiable. Such a regulatory process is unsatisfactory and may undermine the credibility of the analyst.Because of the technical difficulty and expense of medication control, the strategy of no control for some medications is an option which requires careful evaluation.