Development and Application of a Physiologically Based Pharmacokinetic Model for Diclazuril in Broiler Chickens

SIMPLE SUMMARY: Coccidiosis is a devastating poultry disease with significant economic implications. The prevention and control of coccidiosis currently rely on the administration of anticoccidial drugs through feed or water. One of the commonly used drugs is diclazuril, which was approved in broilers for their whole life. Additionally, its prolonged use can lead to residue accumulation in edible tissues. As a result, we developed and validated a physiologically based pharmacokinetic (PBPK) model for diclazuril to predict its residues in broilers. We identified and analyzed the key parameters associated with diclazuril concentrations in the muscle through Monte Carlo analysis. Our findings suggested that a withdrawal period of 0 days was suitable for both recommended dosing regimens. This model can be expanded to other coccidiostats and poultry species as a critical resource. ABSTRACT: Withdrawal periods for diclazuril in broilers have traditionally been determined through regression analysis. However, over the last two decades, the physiologically based pharmacokinetic (PBPK) model has gained prominence as a predictive tool for veterinary drug residues, which offers an alternative method for establishing appropriate withdrawal periods for veterinary drugs. In this current study, a flow-limited PBPK model was developed to predict diclazuril concentrations in broilers following long-duration administration via medicated feed and water. This model consists of nine compartments, including arterial and venous plasma, lung, muscle, skin + fat, kidney, liver, intestine contents, and the rest of the body compartment. Physiological parameters such as tissue weights (V(cxx)) and blood flow (Q(cxx)) were gathered from published studies, and tissue/plasma partition coefficients (P(xx)) were calculated through the area method or parameter optimization. Published diclazuril concentrations were compared to the predicted values, indicating the accuracy and validity of the model. The sensitivity analysis showed that parameters associated with cardiac output, drug absorption, and elimination significantly affected diclazuril concentrations in the muscle. Finally, a Monte Carlo analysis, consisting of 1000 iterations, was conducted to calculate the withdrawal period. Based on the Chinese MRL values, we calculated a withdrawal period of 0 days for both recommended dosing regimens (through mediated water and feed at concentrations of 0.5–1 mg/L and 1 mg/kg, respectively). However, based on the European MRLs, longer periods were determined for the mediated feed dosing route. Our model provides a foundation for scaling other coccidiostats and poultry species.