Food safety: the intersection of pharmacometrics and veterinary medicine
Jim E. Riviere
Institute of Computational Comparative Medicine, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA
Food animal veterinarians bear numerous responsibilities, not only to their sick patients, but also to the producers and consumers of animal food products, as well as the environment. A fundamental difference between food animal veterinary and human medicine relates to the fact that animals treated with drugs are often consumed as food after treatment is completed.
Unlike for humans where the physician isn't concerned about drug left in the patient after treatment, in food animal medicine the veterinarian must be sure an effective dose of drug is given (appropriate PK-PD regimen) and also that no potentially adverse levels of drug persist in the edible tissues and products (e.g. milk, eggs) of treated animals. A second difference is that drugs are administered to large populations of animals as disease is often diagnosed and treated on a herd basis.
Animals may be dosed in feed, water or dips, creating uncertainty in dose level and interval. Uncontrollable environmental covariates like temperature and humidity can further increase variability. These factors must be considered to insure that a safe food animal product free of toxic or allergic chemicals reaches the consumer. The regulatory determination of such tissue withdrawal times is performed in control groups of healthy animals. Although the pharmacometric approaches to the calculation of such parameters in various regulatory jurisdictions may differ, the experimental design of such trials is similar. Once approved, drugs are then used in natural clinical populations where diseases processes for which the drug is labeled to treat are present, and concomitant medications are also often administered. This has resulted in a regulatory system with a reasonable degree of reproducibility relative to determination of the withdrawal time metric, but a lack of direct relationship to drug disposition processes seen in clinical populations of animals treated under diverse conditions.
Various authors have amply reviewed the impact of disease processes on the primary drug pharmacokinetic parameters, with focus being on drug elimination and distribution pathways and processes as they affect blood concentration-time profiles as a function of drug efficacy. However, the effect of such factors on very low residue-level concentrations (PPM, PPB) of drugs and their metabolites in edible tissues has rarely been addressed or even considered. Similarly, residue depletion trials are often conducted in homogeneous groups of animals using controlled dosing regimens in order to reduce animal numbers while still arriving at a statistical solution to the withdrawal time algorithm; yet variability in the actual treated populations relative to breed, production and environmental factors alone easily violates this assumption. This is particularly true when the withdrawal time algorithm is attempting to estimate behavior in 1-5% of the population with 95% confidence. Situations where concern arises include when the disease process alters the normal ratio of parent drug to marker residue produced by altered biotransformation processes, when a product of the disease process binds to and modifies the drug residue depletion profile in a target tissue, or when disposition processes fundamentally alter pharmacokinetic patterns.
Advances in population (mixed effect) pharmacokinetic modeling open up approaches to study, model and predict these factors; in many cases directly based on the mechanism of the interaction. Mixed effect models allow disease related and potentially pharmacogenomic factors to be directly estimated and modeled. Such considerations become increasingly important if global regulatory jurisdictions set residue tolerances based on the limits of analytical detection, which of late continually drops to levels where minor interactions at the molecular tissue level become important for model predictions and violations of tissue tolerances, but are totally irrelevant to their toxicological impact on human food safety.