Food Animal Residue Avoidance Databank Research Articles

Development of machine learning-based quantitative structure–activity relationship models for predicting plasma half-lives of drugs in six common food animal species

Abstract Plasma half-life is a crucial pharmacokinetic parameter for estimating extralabel withdrawal intervals of drugs to ensure the safety of food products derived from animals. This study focuses on developing a quantitative structure–activity relationship (QSAR) model incorporating multiple machine learning and artificial intelligence algorithms, and aims to predict the plasma half-lives of drugs in 6 food animals, including cattle, chickens, goats, sheep, swine, and turkeys. By integrating 4 machine learning algorithms with 5 molecular descriptor types, 20 QSAR models were developed using data from the Food Animal Residue Avoidance Databank (FARAD) Comparative Pharmacokinetic Database. The deep neural network (DNN) algorithm demonstrated the best prediction ability of plasma half-lives. The DNN model with all descriptors achieved superior performance with a high coefficient of determination (R2) of 0.82 ± 0.19 in 5-fold cross-validation on the training sets and an R2 of 0.67 on the independent test set, indicating accurate predictions and good generalizability. The final model was converted to a user-friendly web dashboard to facilitate its wide application by the scientific community. This machine learning-based QSAR model serves as a valuable tool for predicting drug plasma half-lives and extralabel withdrawal intervals in 6 common food animals based on physicochemical properties. It also provides a foundation to develop more advanced models to predict the tissue half-life of drugs in food animals.

Diagnosis and management of obstructive urolithiasis in miniature pigs.

This article provides information to assist practitioners in the diagnosis, medical, and surgical management of obstructive urolithiasis in miniature pigs. The article focuses primarily on pigs managed as pets because production swine rarely undergo intensive treatment for urolithiasis. As much as possible, the information in this article is based on published literature, but given the limited number of publications addressing obstructive urolithiasis in pigs, some information is based on the authors' clinical experience. Medical and surgical management of obstructive urolithiasis of pigs is often similar to management in ruminant and small animal species, but differences in swine anatomy, handling, and temperament create unique challenges. Pigs tend to be more difficult to restrain and examine than other livestock and often require heavy sedation or anesthesia to facilitate physical examination and basic diagnostic procedures. Because pigs are monogastrics, some oral treatments used in small animals may be used effectively in pigs. Clinicians should follow AMDUCA and consult the Food Animal Residue Avoidance Databank prior to extralabel drug use because pet pigs are still considered a major food-producing species in the United States.

An Interactive Generic Physiologically Based Pharmacokinetic (igPBPK) Modeling Platform to Predict Drug Withdrawal Intervals in Cattle and Swine: A Case Study on Flunixin, Florfenicol, and Penicillin G.

Violative chemical residues in edible tissues from food-producing animals are of global public health concern. Great efforts have been made to develop physiologically based pharmacokinetic (PBPK) models for estimating withdrawal intervals (WDIs) for extralabel prescribed drugs in food animals. Existing models are insufficient to address the food safety concern as these models are either limited to 1 specific drug or difficult to be used by non-modelers. This study aimed to develop a user-friendly generic PBPK platform that can predict tissue residues and estimate WDIs for multiple drugs including flunixin, florfenicol, and penicillin G in cattle and swine. Mechanism-based in silico methods were used to predict tissue/plasma partition coefficients and the models were calibrated and evaluated with pharmacokinetic data from Food Animal Residue Avoidance Databank (FARAD). Results showed that model predictions were, in general, within a 2-fold factor of experimental data for all 3 drugs in both species. Following extralabel administration and respective U.S. FDA-approved tolerances, predicted WDIs for both cattle and swine were close to or slightly longer than FDA-approved label withdrawal times (eg, predicted 8, 28, and 7 days vs labeled 4, 28, and 4 days for flunixin, florfenicol, and penicillin G in cattle, respectively). The final model was converted to a web-based interactive generic PBPK platform. This PBPK platform serves as a user-friendly quantitative tool for real-time predictions of WDIs for flunixin, florfenicol, and penicillin G following FDA-approved label or extralabel use in both cattle and swine, and provides a basis for extrapolating to other drugs and species.

Development and Application of an Interactive Physiologically Based Pharmacokinetic (iPBPK) Model to Predict Oxytetracycline Tissue Distribution and Withdrawal Intervals in Market-Age Sheep and Goats.

Oxytetracycline (OTC) is a widely used antibiotic in food-producing animals. Extralabel use of OTC is common and may lead to violative residues in edible tissues. It is important to have a quantitative tool to predict scientifically based withdrawal intervals (WDIs) after extralabel use in food animals to ensure human food safety. This study focuses on developing a physiologically based pharmacokinetic (PBPK) model for OTC in sheep and goats. The model included 7 compartments: plasma, lung, liver, kidneys, muscle, fat, and rest of the body. The model was calibrated with serum and tissue (liver, muscle, kidney, and fat) concentration data following a single intramuscular (IM, 20 mg/kg) and/or intravenous (IV, 10 mg/kg) administration of a long-acting formulation in sheep and goats. The model was evaluated with independent datasets from Food Animal Residue Avoidance Databank (FARAD). Results showed that the model adequately simulated the calibration datasets with an overall estimated coefficient of determination (R2) of 0.95 and 0.92, respectively, for sheep and goat models and had acceptable accuracy for the evaluation datasets. Monte Carlo sampling technique was applied to predict the time needed for drug concentrations in edible tissues to fall below tolerances for the 99th percentiles of the population. The model was converted to a web-based interactive PBPK (iPBPK) interface to facilitate model applications. This iPBPK model provides a useful tool to estimate WDIs for OTC after extralabel use in small ruminants to ensure food safety and serves as a basis for extrapolation to other tetracycline drugs and other food animals.

Producer and Veterinarian Perspectives towards Pain Management Practices in the US Cattle Industry.

Simple SummaryA key aspect to improve animal welfare is to reduce pain experienced by the animal. However, pain management practices have not been widely adopted in the United States (US) cattle industry. Furthermore, for a veterinarian or producer to relieve pain in cattle, analgesics must be provided in an extra-label drug manner. Currently, research describing pain mitigation strategies used by cattle producers and the study of barriers to implement those strategies from a producer or veterinarian perspective is limited. Understanding challenges faced by these stakeholders is key in improving on-farm pain management strategies. Therefore, the objectives of this study were to explore producer and veterinarian perspectives on pain. Albeit analgesia use increased in the past ten years for some producers and the majority of veterinarians, administering analgesics for pain management on US cattle farms remains a challenge. From a producer perspective, drug cost, availability and logistics for administration. From a veterinarian perspective, lack of Food and Drug Administration (FDA) products hinders the support of on-farm protocols requiring extra-label drug use. Future steps to improve analgesic use on-farm include identifying and approving drugs that demonstrate efficacy for managing pain and disseminating educational resources to support stakeholders in both the implementation and drug withdrawal process.Producers and veterinarians are considered responsible for improving animal welfare, as they are responsible for implementing practices that directly impact the animal’s well-being. Most husbandry procedures performed in cattle do not include pain mitigation, and understanding challenges faced by these stakeholders to use analgesics is key in improving on-farm pain management strategies. Therefore, the objectives of this study were to explore producer and veterinarian perspectives on pain management practices by (1) exploring inquires received by Food Animal Residue Avoidance Databank (FARAD) regarding analgesic use in cattle and (2) using a survey instrument to identify factors that impact pain management implementation in the US cattle industry. Albeit analgesia use increased in the past ten years for some producers and the majority of veterinarians, administering analgesics for pain management on US cattle farms remains a challenge. From a producer perspective, drug cost, availability and logistics for administration. From a veterinarian perspective, lack of Food and Drug Administration (FDA) products hinders the support of on-farm protocols requiring extra-label drug use. Future steps to improve analgesic use on-farm include identifying and approving drugs that demonstrate efficacy for managing pain in cattle and disseminating educational resources to support stakeholders in both the implementation and drug withdrawal process.

Integration of Food Animal Residue Avoidance Databank (FARAD) empirical methods for drug withdrawal interval determination with a mechanistic population-based interactive physiologically based pharmacokinetic (iPBPK) modeling platform: example for flunixin meglumine administration.

Violative chemical residues in animal-derived food products affect food safety globally and have impact on the trade of international agricultural products. The Food Animal Residue Avoidance Databank program has been developing scientific tools to provide appropriate withdrawal interval (WDI) estimations after extralabel drug use in food animals for the past three decades. One of the tools is physiologically based pharmacokinetic (PBPK) modeling, which is a mechanistic-based approach that can be used to predict tissue residues and WDIs. However, PBPK models are complicated and difficult to use by non-modelers. Therefore, a user-friendly PBPK modeling framework is needed to move this field forward. Flunixin was one of the top five violative drug residues identified in the United States from 2010 to 2016. The objective of this study was to establish a web-based user-friendly framework for the development of new PBPK models for drugs administered to food animals. Specifically, a new PBPK model for both cattle and swine after administration of flunixin meglumine was developed. Population analysis using Monte Carlo simulations was incorporated into the model to predict WDIs following extralabel administration of flunixin meglumine. The population PBPK model was converted to a web-based interactive PBPK (iPBPK) framework to facilitate its application. This iPBPK framework serves as a proof-of-concept for further improvements in the future and it can be applied to develop new models for other drugs in other food animal species, thereby facilitating the application of PBPK modeling in WDI estimation and food safety assessment.

Extended withdrawal time (EWDT) of drugs to prevent residues in food following extra label use

Safety of food originated from animals is an emerging global health problem, and ensuring food safety is a challenge for the producers and governments who deal with protecting the food supply chain from contamination with hazardous microbes, chemicals and/or drugs. In the United States (US), the Food Animal Residue Avoidance Databank (FARAD) program is a unique consortium of scientific experts who help maintain a proper balance among animal health, food safety, and regulatory policies. Veterinarians must often use drugs in an extra-label manner to treat food animals due to limited availability of Food and Drug Administration (FDA) approved drugs. Extra-label drug use (ELDU) is allowable under the Animal Medicinal Drug Use Clarification Act (AMDUCA). Following ELDU, and before products derived from the treated animal can be sold and marketed, an extended withdrawal time (EWDT) needs to be established, based on appropriate scientific data. The objective of this paper is to discuss the scientific basis for determination of EWDT of drugs used in food animals using kinetic modeling approach.

Development and application of a population physiologically based pharmacokinetic model for penicillin G in swine and cattle for food safety assessment

Penicillin G is a widely used antimicrobial in food-producing animals, and one of the most predominant drug residues in animal-derived food products. Due to reduced sensitivity of bacteria to penicillin, extralabel use of penicillin G is common, which may lead to violative residues in edible tissues and cause adverse reactions in consumers. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict drug residues in edible tissues and estimate extended withdrawal intervals for penicillin G in swine and cattle. A flow-limited PBPK model was developed with data from Food Animal Residue Avoidance Databank using Berkeley Madonna. The model predicted observed drug concentrations in edible tissues, including liver, muscle, and kidney for penicillin G both in swine and cattle well, including data not used in model calibration. For extralabel use (5× and 10× label dose) of penicillin G, Monte Carlo sampling technique was applied to predict times needed for tissue concentrations to fall below established tolerances for the 99th percentile of the population. This model provides a useful tool to predict tissue residues of penicillin G in swine and cattle to aid food safety assessment, and also provide a framework for extrapolation to other food animal species.

Review of AMDUCA and Extra-Label Drug Use in Food Animals

This presentation will review the Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994 and how the Food Animal Residue Avoidance Databank (FARAD) provides scientifically-based residue withholding information within the context of extra-label drug use guidelines. Several beef and dairy cases will be presented to demonstrate FARAD’s successes and challenges to minimize violative drug residues in animal-derived food products. Finally, several of the research initiatives developed by FARAD scientists that have improved withdrawal time estimation will be reviewed within the context of extra-label drug use in food animals.

Elimination Kinetics of Tilmicosin Following Intramammary Administration in Lactating Dairy Cattle

Tilmicosin is a macrolide antibiotic approved for both the treatment and control of respiratory disease in beef cattle and dairy cattle under 20 months of age. The drug is not approved for use in lactating dairy cattle; however, tilmicosin is sometimes used in an extralabel manner by bovine practitioners for the intramammary treatment of mastitis. This practice results in detectible residues and has resulted in several instances of milk residue violation referred to the Food Animal Residue Avoidance Databank (FARAD). The purpose of this study was to determine the elimination kinetics of tilmicosin in milk following an intramammary infusion so an appropriate proper milk withdrawal interval could be determined.

Development of a physiologic-based pharmacokinetic model for estimating sulfamethazine concentrations in swine and application to prediction of violative residues in edible tissues

To develop a flow-limited, physiologic-based pharmacokinetic model for use in estimating concentrations of sulfamethazine after IV administration to swine. 4 published studies provided physiologic values for organ weights, blood flows, clearance, and tissue-to-blood partition coefficients, and 3 published studies provided data on plasma and other tissue compartments for model validation. For the parent compound, the model included compartments for blood, adipose, muscle, liver, and kidney tissue with an extra compartment representing the remaining carcass. Compartments for the N-acetyl metabolite included the liver and the remaining body. The model was created and optimized by use of computer software. Sensitivity analysis was completed to evaluate the importance of each constant on the whole model. The model was validated and used to estimate a withhold interval after an IV injection at a dose of 50 mg/kg. The withhold interval was compared to the interval estimated by the Food Animal Residue Avoidance Databank (FARAD). Specific tissue correlations for plasma, adipose, muscle, kidney, and liver tissue compartments were 0.93, 0.86, 0.99, 0.94, and 0.98, respectively. The model typically overpredicted concentrations at early time points but had excellent accuracy at later time points. The withhold interval estimated by use of the model was 120 hours, compared with 100 hours estimated by FARAD. Use of this model enabled accurate prediction of sulfamethazine pharmacokinetics in swine and has applications for food safety and prediction of drug residues in edible tissues.

Antidotes in food animal practice

1Because there is little economic incentive for pharmaceutical companies to pursue antidote approval for a limited market, it is unlikely that this situation will change in the near future. In most instances, practitioners seeking to treat food animals for toxicoses are compelled to either use products in an extralabel manner or to compound antidotes from bulk sources. There are relatively few data from which scientifically based withdrawal intervals (WDIs) may be developed for the protection of human health. This Food Animal Residue Avoidance Databank (FARAD) Digest provides a summary of regulatory and scientific information regarding the most commonly recommended antidotes used in food animals. None of the drugs covered in this digest have been approved by the FDA Center for Veterinary Medicine (FDA/CVM) as New Animal Drugs. The information on residues presented in this digest is for the antidotes, not for the toxicants. When an antidote must be used to treat a food animal for a toxicosis, a WDI to ensure depletion of the toxicant is also required, and it may be longer than the WDI for the antidote. FARAD can provide WDI recommendations for a wide range of toxicants; however, these recommendations must be made on a case-by-case basis because of differences in exposure route, dose, and duration. Unapproved Veterinary Antidotes Marketed with Veterinary Labels The FDA/CVM has applied regulatory discretion and does not prohibit the commercial manufacture and marketing of several veterinary antidotes. These products do not have New Animal Drug Approval (NADA) numbers and have not been formally approved by the FDA/CVM. These products are manufactured under Good Manufacturing Practices, and their labels are reviewed and on file with the FDA/CVM. They may be used as antidotes in food animals, although higher dosages or more prolonged treatment than that indicated on the labels may be necessary. Animal Medicinal Drug Use Clarification Act requirements do not apply to these drugs because they are not approved drugs; however, veterinarians are strongly encouraged to follow AMDUCA requirements when using these drugs. 2

A web-based decision support system to estimate extended withdrawal intervals

All drugs approved for use in food-producing animals have a withdrawal interval to prevent residues in food of animal origin that are potentially harmful to consumers. These withdrawal times must be appropriately extended if the drug is used in an extralabel manner. This paper describes a web-based application that was developed to facilitate the calculation of extended withdrawal intervals based on information in the databases maintained by members of the Food Animal Residue Avoidance Databank (FARAD) and using the Extrapolated Withdrawal Interval Estimator (EWE) algorithm. The implementation of this application was illustrated using a group of antimicrobials that are used in cattle and swine. The use of this application has been limited to staff veterinarians working for FARAD since limitations in the available pharmacokinetic data require that results are interpreted by personnel with in-depth knowledge of the pharmacokinetics of drugs in food-producing animals.

Evaluation of the advisory services provided by the Food Animal Residue Avoidance Databank

Evaluation of the advisory services provided by the Food Animal Residue Avoidance Databank

Interspecies considerations in the evaluation of human food safety for veterinary drugs.

Residues are composed of the parent drug and metabolites, and therefore interspecies comparisons must involve a consideration of comparative xenobiotic metabolism. The focus of this article will be the residue studies that are required to establish human food safety, and the interspecies pharmacokinetic differences and similarities that impact drug residues in animal- derived foods. To illustrate the factors that can complicate and assist these comparisons, 2 drugs will be examined in detail: ivermectin and fenbendazole. In addition, the activities of 2 US programs, the Food Animal Residue Avoidance Databank (FARAD) and the NRSP-7 (National Research Support Project Number 7) Minor Use Animal Drug Program will be presented, along with strategies that may be employed in the study of species differences.

Extrapolated Withdrawal-Interval Estimator (EWE) Algorithm: A Quantitative Approach to Establishing Extralabel Withdrawal Times

The extralabel use of drugs can be defined as the use of drugs in a manner inconsistent with their FDA-approved labeling. The passage of the Animal Medicinal Drug Use Clarification Act (AMDUCA) in 1994 and its implementation by the FDA—Center for Veterinary Medicine in 1996 has allowed food animal veterinarians to use drugs legally in an extralabel manner, as long as an appropriate withdrawal period is established. The present study introduces and validates with simulated and experimental data the Extrapolated Withdrawal-Period Estimator (EWE) Algorithm, a procedure aimed at predicting extralabel withdrawal intervals (WDIs) based on the label and pharmacokinetic literature data contained in the Food Animal Residue Avoidance Databank (FARAD). This is the initial and first attempt at consistently obtaining WDI estimates that encompass a reasonable degree of statistical soundness. Data on the determination of withdrawal times after the extralabel use of the antibiotic oxytetracycline were obtained both with simulated disposition data and from the literature. A withdrawal interval was computed using the EWE Algorithm for an extralabel dose of 25 mg/kg (simulation study) and for a dose of 40 mg/kg (literature data). These estimates were compared with the withdrawal times computed with the simulated data and with the literature data, respectively. The EWE estimates of WDP for a simulated extralabel dose of 25 mg/kg was 39 days. The withdrawal time (WDT) obtained for this dose on a tissue depletion study was 39 days. The EWE estimate of WDP for an extralabel intramuscular dose of 40 mg/kg in cattle, based on the kinetic data contained in the FARAD database, was 48 days. The withdrawal time experimentally obtained for similar use of this drug was 49 days. The EWE Algorithm can obtain WDI estimates that encompass the same degree of statistical soundness as the WDT estimates, provided that the assumptions of the approved dosage regimen hold for the extralabel dosage regimen. Population models could be fitted to fragmentary data to predict residue concentrations in tissues, validate the EWE estimates, and obtain WDI estimates.

Mixed‐effects modeling of the interspecies pharmacokinetic scaling of oxytetracycline

Differences in the disposition of certain drugs across mammalian species often arise because of their diverse physiology and anatomical characteristics. Factors such as body mass, brain weight, and maximum lifespan are related to the way that different species of mammals handle drugs. Drug disposition data can be scaled across species when chronological time is substituted by the appropriate measure of pharmacokinetic time. In this study, we developed allometric scaling models for oxytetracycline, using serum disposition data obtained from the Food Animal Residue Avoidance Databank. The data were modeled using the mixed‐effects modeling approach. The models obtained were validated using disposition data on swine. Oxytetracycline scaled across species based on body weight and the best interspecies model adequately predicted the value of the pharmacokinetic parameters across species. The population approach allows one to estimate the allometric coefficients and exponents of the pharmacokinetic parameters to obtain a model that best fits the multi‐species pooled concentration–time data. Furthermore, this approach allows decisions to be made based on the statistical significance of the parameter estimates and the adequacy of the models that are not possible with traditional approaches.

Mixed effects modeling of the disposition of gentamicin across domestic animal species.

An interspecies pharmacokinetic model for gentamicin was developed using the mixed effects modeling approach and serum disposition data obtained from the Food Animal Residue Avoidance Databank (FARAD). Data that met a priori quality criteria was obtained from the database and analysed using the traditional double logarithmic analysis and the mixed effects modeling approach. Body weight, brain weight and fever were the covariates of interest in our study. Population pharmacokinetic models across species were developed and validated with swine data. The parameter volume of distribution was modeled as a function of body weight. The total clearance was initially modeled as a function of body weight. The predictability performance of the model improved dramatically when the parameter brain weight was included in the covariate model for clearance. This was a surprising finding worthy of further study. The covariate fever seemed to influence the magnitude of the volume of distribution, although the scarcity of data pertaining to diseased animals makes this finding uncertain. We conclude that the pharmacokinetic characteristics of drugs such as gentamicin, can be predicted across species using a population pharmacokinetics modeling approach, and that clinical features that affect species in a similar manner can be also explored in this fashion.

The Food Animal Residue Avoidance Databank (Farad): Past, Present and Future

During the last one-and-one-half decades, FARAD has established an unparalleled compilation of residue and pharmacokinetic information for veterinary species. In order to fulfill its mission, FARAD has become as much a research project as an educational one. Pressing problems, such as disease-altered kinetics, minor-species drug use, and industrial contaminants in livestock, require the new methods of analysis FARAD is developing. The data upon which this work is based can be greatly augmented by participation by other nations. In the United States, it was the cooperation of both academic and regulatory organizations that made the success of FARAD possible. Similar international cooperation can facilitate use of the FARAD model in other countries for the economic benefit of all participants, enhancement of food safety, and promotion of animal welfare.

Use of the Food Animal Residue Avoidance Databank (FARAD)

Objectives To report the results of 3 surveys evaluating the extent that the Food Animal Residue Avoidance Databank (FARAD) is used by veterinarians, the profession's perception of the need for the program, barriers that prevent veterinarians from fully using the service, and the perceptions that animal production industry groups have regarding FARAD. Design Telephone and mail surveys were used to collect information using cross-sectional, case-control, and directed sample studies. Sample Population Food animal veterinarians and veterinarians and nonveterinarians in allied animal industries or with special interest in production animal medicine. Results The use of FARAD was high among dairy and general practitioners, but low among beef practitioners and veterinarians with minor commitment to food animal medicine. Solo practitioners and veterinarians with less than 13 years in practice were less likely to use FARAD. Dairy practitioners who had not used FARAD were most likely to prescribe extralabel products. Clinical Implications Results imply that dairy and general food animal practitioners have either greater need or access through educational networks and are more aware of FARAD than practitioners who work with beef and those with a minor component of their practice involving food animals. The difference in familiarity and use of FARAD between practice type is an important finding, but the root of the difference is not clear; it may be attributable to a difference in the effectiveness of knowledge transfer for the groups, or the message is ignored because the issue of drug residues is less compelling for veterinarians and their clients in the beef sector. (J Am Vet Med Assoc 1999;214:344–350)