Applications of PBPK Models to Predict Tissue Residues and Extralabel Withdrawal Times of Drugs in Food Animals: Perspectives from the Food Animal Residue Avoidance Databank (FARAD) Program.

Physiologically based pharmacokinetic (PBPK) models are commonly used in human drug discovery and development and human health risk assessment of environmental chemicals. One emerging application of PBPK models is to predict tissue residues and withdrawal times of drugs in food animals, which is important for human food safety assessment of animal-derived food products, such as meat, milk, and eggs. This review summarizes existing guidelines to establish the regulatory agency approved label withdrawal period and available pharmacometric methods to predict extralabel withdrawal times, with a focus on PBPK modeling. We conducted a comprehensive literature search on existing PBPK models in food animals. Two hundred thirteen PBPK models in different food animal species (e.g., cattle, swine, sheep, goats, and chickens) from 113 publications were identified. The general procedure to build a PBPK model for a drug in food animals to predict withdrawal times is summarized. Differences in PBPK modeling between humans and food animals and between different food animal species are discussed. Novel uses of PBPK models to predict extralabel withdrawal times are illustrated with recent case studies from the Food Animal Residue Avoidance Databank (FARAD). Recent advances and challenges in PBPK modeling in food animals are discussed, followed by our future perspectives on how to develop more robust PBPK models for food animals to address the safety assessment of animal-derived food products.