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

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.

Keywords: broiler chickens; diclazuril; physiologically based pharmacokinetic (PBPK) model; residue prediction; withdrawal interval.

Figure 1

Schematic diagram of the physiologically based pharmacokinetic model for diclazuril in broiler chickens after oral administration. Q_xx (L/h) is plasma flow through some tissue. Subscript xx is the name of tissue, and lu, mu, sf, li, ki, and re were abbreviations for lung, muscle, skin + fat, liver, kidney, and the rest of the body compartment, respectively. Based on previous studies [1,19,20,22], diclazuril was orally given to chickens through medicated feed or water. It was assumed that all diclazuril was immediately available in the intestinal tract after dosing, and from there, diclazuril was absorbed with the rate constant of K_a (h⁻¹). The unabsorbed diclazuril was eliminated with feces at the rate of K_gut (h⁻¹). In addition to intestinal elimination, the parameter of Cl_he (L/h/kg) was used to simulate the hepatic elimination of diclazuril.

Figure 2

Comparisons between predicted (curves) and published (points; [22]) diclazuril concentrations (μg/kg) in tissues after 10 consecutive days of administering medicated feed containing 730 μg/kg of diclazuril.

Figure 3

Comparisons between predicted (curves) and published (points; [22]) diclazuril concentrations (μg/kg or μg/L) in tissues and plasma after 9 consecutive days of administering medicated water containing 3 mg/kg of diclazuril.

Figure 4

Sensitivity analysis results for those influential parameters on diclazuril concentrations in muscle.