Use of a Monte Carlo analysis within a physiologically based pharmacokinetic model to predict doxycycline residue withdrawal time in edible tissues in swine

Abstract

The pharmacokinetics of doxycycline were studied following a single intravenous (I.V.) and intramuscular (I.M.) injection of 10 mg/kg into eight healthy pigs. The steady-state tissue/plasma partition coefficients were obtained via a 3-h constant rate infusion (CRI) in four pigs. Based on the results of in vivo studies and the parameters derived from published work, a physiologically based pharmacokinetic (PBPK) model was developed to predict the drug concentration in edible tissues. The predicted values were then compared with those derived from a previous study. To account for individual differences in the processes of drug metabolism and/or diffusion, a Monte Carlo (MC) run of 1000 simulations was incorporated into the PBPK model to predict the doxycycline residue withdrawal times in edible tissues in swine. The withdrawal periods were compared with those derived from linear regression analysis. The PBPK model presented here provided accurate predictions of the observed concentrations in all tissues except for the injection site. The withdrawal times in all edible tissues derived from the MC analysis were longer than those from linear regression analysis. Based on the residues in the injection site and muscle tissue, the MC analysis predicted a withdrawal time of 33 days. Here, we illustrate that MC analysis can be incorporated into the PBPK model to accurately predict doxycycline residue withdrawal time in edible tissues in swine.