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

Abstract

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.