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Mequindox (MEQ) is a quinoxaline-N,N-dioxide antibiotic used in food-producing animals. MEQ residue in animal-derived foods is a food safety concern. The tissue distribution of MEQ and its marker residue 1,4-bisdesoxymequindox (M1) were determined in swine following oral gavage or intramuscular injection twice daily for 3 days. The experimental data were used to construct a flow-limited physiologically based pharmacokinetic (PBPK) model. The model predictions correlated with available data well. Monte Carlo analysis showed that the times needed for M1 concentrations to fall below limit of detection (5 μg/kg) in liver for the 99th percentile of the population were 27 and 34 days after oral gavage and intramuscular administration twice daily for 3 days, respectively. This population PBPK model can be used to predict depletion kinetic profiles and tissue residues of MEQ's marker residue M1 in swine and as a foundation for scaling to other quinoxaline-N,N-dioxide antibiotics and to other animal species.

The aim of this manuscript is to review the potential adverse health effects in humans if exposed to residues of selected veterinary drugs used in food-producing animals. Our other objectives are to briefly inform the reader of why many of these drugs are or were approved for use in livestock production and how drug residues can be mitigated for these drugs. The selected drugs include several antimicrobials, beta agonists, and phenylbutazone. The antimicrobials continue to be of regulatory concern not only because of their acute adverse effects but also because their use as growth promoters have been linked to antimicrobial resistance. Furthermore, nitroimidazoles and arsenicals are no longer approved for use in food animals in most jurisdictions. In recent years, the risk assessment and risk management of beta agonists, have been the focus of national and international agencies and this manuscript attempts to review the pharmacology of these drugs and regulatory challenges. Several of the drugs selected for this review can cause noncancer effects (e.g., penicillins) and others are potential carcinogens (e.g., nitroimidazoles). This review also focuses on how regulatory and independent organizations manage the risk of these veterinary drugs based on data from human health risk assessments., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Allometric scaling is widely used for the determination of first dosage regimen and the interpolation or extrapolation of pharmacokinetic parameters across many animal species during drug development. In this article, 85 drugs used in veterinary medicine obtained from the Food Animal Residue Avoidance Databank database were selected for allometric scaling analysis. Outlier species were identified by statistical methods. The results showed that 77% and 88% of drugs displayed significant correlations between total systemic clearance (CL) and volume of distribution at steady status (Vss) vs. body weight (P < 0.05) on a log-log scale, respectively. The distribution of the allometric exponent b for CL and Vss displays approximate normal distribution, with means (0.87 and 0.99) and standard deviations (0.143 and 0.157) for CL and Vss, respectively. Twelve drugs were identified to have at least one outlier species for CL and ten drugs for Vss. The human CL and Vss were predicted for selected drugs by the obtained allometric equations. The predicted CL and Vss were within a threefold error compared to observed values, except the predicted CL values for antipyrine, warfarin and diazepam. The results can be used to estimate cross-species pharmacokinetic profiles for predicting drug dosages in veterinary species, and to identify those species for which interpolation or extrapolation of pharmacokinetics properties may be problematic., (© 2014 John Wiley & Sons Ltd.)

Twenty lactating dairy cattle were intravenously infused with either lipopolysaccharide (LPS) (n = 10) or sterile saline (n = 10). Five cattle in each group received three doses of flunixin meglumine administered by either intravenous infusion or intramuscular injection at 24 h intervals. Milk, urine, and tissues were collected. Thirty-six hours after the last flunixin administration, milk from six cows contained 5-hydroxyflunixin (5OHF) levels greater than the milk tolerance of 2 ng/mL; by 48 h, milk from two cows, a saline and a LPS-treated animal, had violative milk concentrations of 5OHF. A single animal treated with LPS and intramuscular flunixin contained violative flunixin residues in liver. The ratio of urinary flunixin/5OHF was correlated (P < 0.01; R(2) = 0.946) with liver flunixin residues in LPS-treated animals, but not (P = 0.96; R(2) = 0.003) in cows treated with saline in lieu of LPS. Violative residues of flunixin in dairy cattle may be related to LPS inhibition of flunixin metabolism.

Combining data from available studies is a useful approach to interpret the overwhelming amount of data generated in medical research from multiple studies. Paradoxically, in veterinary medicine, lack of data requires integrating available data to make meaningful population inferences. Nonlinear mixed-effects modeling is a useful tool to apply meta-analysis to diverse pharmacokinetic (PK) studies of veterinary drugs. This review provides a summary of the characteristics of PK data of veterinary drugs and how integration of these data may differ from human PK studies. The limits of meta-analysis include the sophistication of data mining, and generation of misleading results caused by biased or poor quality data. The overriding strength of meta-analysis applied to this field is that robust statistical analysis of the diverse sparse data sets inherent to veterinary medicine applications can be accomplished, thereby allowing population inferences to be made., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Physiologically based pharmacokinetic (PBPK) models are powerful tools to predict tissue distribution and depletion of veterinary drugs in food animals. However, most models only simulate the pharmacokinetics of the parent drug without considering their metabolites. In this study, a PBPK model was developed to simultaneously describe the depletion in pigs of the food animal antimicrobial agent cyadox (CYA), and its marker residue 1,4-bisdesoxycyadox (BDCYA). The CYA and BDCYA sub-models included blood, liver, kidney, gastrointestinal tract, muscle, fat and other organ compartments. Extent of plasma-protein binding, renal clearance and tissue-plasma partition coefficients of BDCYA were measured experimentally. The model was calibrated with the reported pharmacokinetic and residue depletion data from pigs dosed by oral gavage with CYA for five consecutive days, and then extrapolated to exposure in feed for two months. The model was validated with 14 consecutive day feed administration data. This PBPK model accurately simulated CYA and BDCYA in four edible tissues at 24-120 h after both oral exposure and 2-month feed administration. There was only slight overestimation of CYA in muscle and BDCYA in kidney at earlier time points (6-12 h) when dosed in feed. Monte Carlo analysis revealed excellent agreement between the estimated concentration distributions and observed data. The present model could be used for tissue residue monitoring of CYA and BDCYA in food animals, and provides a foundation for developing PBPK models to predict residue depletion of both parent drugs and their metabolites in food animals.

This article explores the numerous challenges encountered when the goal is to demonstrate bioequivalence (BE) between test and reference intramammary (IMM) products in ruminants. Numerous pathophysiological factors of mastitis and physicochemical properties of IMM formulations are implicated in the difficulties in confirming BE for this dosage form. Advantages and disadvantages of current BE study designs are discussed, and alternative perspectives are outlined. Ongoing and future research increasing our knowledge of the pharmacokinetics and pharmacodynamics of antimicrobial drugs delivered through this route is crucial to better understanding the implications of clinically significant formulation differences in the demonstration of BE and may also help in developing more effective IMM formulations for ruminants., (© 2012 Blackwell Publishing Ltd.)

When a drug product remains in the body for a duration of hours or days, estimating the extent of drug exposure is relatively straightforward. For immediate release (IR) dosage forms, the peak drug concentration (C(max)) and time to peak concentrations (T(max)) are typically adequate for comparing product rates of drug absorption. However, unique complexities need to be addressed when a drug remains in the system for a duration of months or years. Specifically, if the long duration of exposure is attributable to formulation effects, C(max) and T(max) may not be adequate to compare the rate of drug absorption, especially when there are multiphasic absorption processes. In this case, it may be appropriate to use partial (segmented areas) for comparing product profiles. However, the decision of how the curves are segmented is not straightforward. Points to consider are discussed in this manuscript. Alternatively, if the long half-life is due to the pharmacokinetics (PK) of the active pharmaceutical ingredient and not to formulation effects, C(max) and T(max) may be appropriate metrics for the rate of absorption but decisions regarding the duration of blood sampling needed to capture the AUC should be based upon an assessment of the inherent variability in drug absorption and elimination. Furthermore, it is important to be confident that the absorption phase is complete. In this manuscript, we explore some of the difficulties associated with determining optimal metrics for comparing the rate and extent of product release for long half life drugs when the long duration of exposure is attributable to either the inherent drug PK or to formulation effects., (© Published 2012. This article is a U.S. Government work and is in the public domain in the USA.)

A risk assessment of the food safety implications of drugs used in food-producing animals is an essential component of the regulatory approval process for products containing these drugs. This ensures that there is negligible risk to human health if these drugs are used according to the instructions that appear on the approved label. A relative paucity of approved products for veterinary species; however, forces veterinarians worldwide to use drugs in an extralabel manner to treat disease and alleviate suffering in animals. In food-producing animals, this may result in residues that are potentially harmful to the human consumer. This review describes how risk assessment principles can be extended to evaluate the risks posed by different classes of extralabel drug use. Risk management practices in the United States and Europe are summarized and contrasted to illustrate the application of these principles.

Under the Animal Medicinal Drug Use Clarification Act of 1994, veterinarians are legally allowed to use drugs in food-producing animals in an extralabel manner. This could potentially lead to violative residues in food of animal origin. It is therefore essential that an appropriately extended withdrawal interval be established. Ideally, these extended withdrawal intervals should be calculated on the basis of the tissue half-life of the drug in the target animal. However, these data are not readily available for all drugs of extralabel use in food-producing animals. For this reason, the use of a half-life multiplier has been proposed as a simple alternative method to estimate the effective tissue half-life of a drug. Extended withdrawal intervals, estimated using various half-life multipliers, were compared with the withdrawal intervals calculated using actual tissue half-lives. For the group of drugs investigated, a half-life multiplier of 5 resulted in estimates of extended withdrawal intervals that were potentially inadequate to prevent violative tissue residues for drugs that had relatively long tissue half-lives, high tolerances, or both. This is possibly because fewer half-lives are required for these drugs to reach the target tissue concentrations following administration at label doses. Use of a smaller half-life multiplier (in this case 3) is therefore suggested to ensure that extended withdrawal intervals are adequate to prevent violative tissue residues.

An overview of reports of suspected adverse drug reactions received by the Veterinary Pharmacovigilance and Medicines Information Centre during the period March 2001 to February 2002 is given. A total of 77 reports were received. The majority of reports involved suspected adverse reactions that occurred in dogs and cats. Most products implicated in the reports were Stock Remedies. The products were predominantly administered either by veterinarians or trained paraveterinary professionals. Although the majority of reports were received from veterinary pharmaceutical companies, the proportion of reports received directly from veterinarians increased compared with previous years.

A study was conducted in the Madikwe District of the North West Province to investigate the supply of veterinary medicinal products to small-scale, subsistence and emerging farmers. A combination of individual interviews, focus groups and direct observation was used to collect data. Stock remedies were made available to farmers within the district at Field Service Units that were managed by administrative staff of the Directorate of Field Services. The state veterinarian and animal health technicians were not directly involved with the sale of products. Most farmers still travelled to farmers' cooperatives in the larger centres outside the district to purchase the veterinary medicinal products they needed. Factors such as the quality of service provided, affordability and availability of required products as well as inaccessibility of outlets to all farmers contributed to the poor support of these outlets by the farmers of the district.

The Veterinary Pharmacovigilance Centre received 59 reports of suspected adverse drug reactions during the period January 1998 - February 2001. The number of reports received increased after the establishment of a formal procedure for recording and responding to reports. The number of reports received per species was: dogs 19, cats 15, cattle 7, sheep/ goats 6, chickens 4, pigs 3, horses 2 and giraffe 1. Many different types of adverse reactions were reported, including lack of efficacy, hypersensitivity, inappropriate use of products by non-veterinarians, known adverse effects and adverse effects encountered with extra-label use of products.

The objective of this study was to investigate the pharmacokinetics and tissue disposition of meloxicam after repeated oral administration in calves. Thirteen male British × Continental beef calves aged 4 to 6 months and weighing 297-392 kg received 0.5 mg/kg meloxicam per os once daily for 4 days. Plasma meloxicam concentrations were determined in 8 calves over 6 days after first treatment. Calves were randomly assigned to be euthanized at 5, 10, 15 (n = 3/timepoint), and 19 days (n = 4) after final administration. Meloxicam concentrations were determined in plasma ( LOQ= 0.025 μg/ mL) and muscle, liver, kidney, and fat samples ( LOQ = 2 ng/g) after extraction using validated LC- MS- MS methods. The mean (± SD) Cmax, Cmin, and Caverage plasma meloxicam concentrations were 4.52 ± 0.87 μg/mL, 2.95 ± 0.77 μg/mL, and 3.84 ± 0.81 μg/ mL, respectively. Mean (± SD) tissue meloxicam concentrations were highest in liver (226.67 ± 118.16 ng/g) and kidney samples (52.73 ± 39.01 ng/g) at 5 days after final treatment. Meloxicam concentrations were below the LOQ in all tissues at 15 days after treatment. These findings suggest that tissue from meloxicam-treated calves will have low residue concentrations by 21 days after repeated oral administration. [ABSTRACT FROM AUTHOR]

Craigmill, A. L., Miller, G. R., Gehring, R., Pierce, A. N., Riviere, J. E. Meta-analysis of pharmacokinetic data of veterinary drugs using the Food Animal Residue Avoidance Databank: oxytetracycline and procaine penicillin G.J. vet. Pharmacol. Therap.27,343–353.Investigators frequently face the quandary of how to interpret the oftentimes disparate pharmacokinetic parameter values reported in the literature. Combining of data from multiple studies (meta-analysis) is a useful tool in pharmacokinetics. Few studies have explored the use of meta-analysis for veterinary species. Even fewer studies have explored the potential strengths and weaknesses of the various methods of performing a meta-analysis. Therefore, in this study we performed a meta-analysis for oxytetracycline (OTC) and procaine penicillin G (PPG) given intramuscularly to cattle. The analysis included 28 individual data sets from 18 published papers for PPG (288 data points), and 41 individual data sets from 25 published papers for OTC (489 data points). Three methods were used to calculate the parameters. The first was a simple statistical analysis of the parameter values reported in each paper. The second method was a standard Two-Stage Method (TSM) using the mean concentration vs. time data extracted from each paper. The third method was the use of nonlinear mixed effect modeling (NMEM) of the concentration vs. time data reported in the various papers, treating the mean data as if each set came from an individual animal. The results of this evaluation indicate that all three methods generate comparable mean parameter estimates for OTC and PPG. The only significant difference noted was for OTC absorption half-lives taken from the published literature, a difference attributable to the use of an alternative method of parameter calculation. The NMEM procedure offers the possibility of including covariates such as dose, age, and weight. In this study the covariates did not influence the derived parameters. A combination approach to meta-analysis of published mean data is recommended, where the TSM is the first step, followed by the NMEM approach. [ABSTRACT FROM AUTHOR]