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

Abstract

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.

Human Food Safety Implications of Variation in Food Animal Drug Metabolism

“…This modeling strategy represents a significant advance in this field because published PBPK models for veterinary drugs all focus on a single drug or one species181920212223. These available models have different model structures that prevent direct comparisons of the pharmacokinetics of different drugs across species.…”

Mathematical modeling and simulation in animal health. Part III: Using nonlinear mixed‐effects to characterize and quantify variability in drug pharmacokinetics

“…Over the past 15 years, several peer‐reviewed NLME analyses in veterinary pharmacology have been published. The most recent examples include the study of topiramate in epileptic dogs (Vuu et al., ); nonsteroidal anti‐inflammatory drug (NSAIDs) in dogs and cats with osteoarthritis (Cox, Liao, Payne‐Johnson, Zielinski, & Stegemann, ; Fink et al., ; Pelligand, Soubret, King, Elliott, & Mochel, ; Silber et al., ); tobramycin in horses (Haritova, Bakalov, Hubenov, & Lashev, ); valnemulin and cefquinome in pigs (Zhao et al., , ); tulathromycin in lactating goats (Lin, Cuneo et al., ; Lin, Gehring et al., ); and penicillin G in cattle and swine (Li et al., ).…”

Development of a multiroute physiologically based pharmacokinetic model for orbifloxacin in rabbits

“…In recent years, there has been an increase in the applications of physiologically based pharmacokinetic (PBPK) models to predict veterinary drug residues (Huang et al., ; Li, Gehring, Riviere, & Lin, ; Yang, Huang, et al., ; Yang et al., ; Yang, Sun, Liu, & Zeng, ; Yang, Sun, et al., ; Yang et al., ; Zeng et al., ). Compared with the traditional monitoring method after animal slaughter, the PBPK model is based on mass‐balance equations defined by physiological mechanisms, and it is predictive in nature and allows for the use of in vitro mechanistic data and population variability data to predict the distribution of drug in animals (Lin, Gehring, Mochel, Lave, & Riviere, ). The existing PBPK models for veterinary drugs mostly contain only one route of administration.…”