Use of probabilistic modeling within a physiologically based pharmacokinetic model to predict sulfamethazine residue withdrawal times in edible tissues in swine

Abstract

The presence of antimicrobial agents in edible tissues of food-producing animals remains a major public health concern. Probabilistic modeling techniques incorporated into a physiologically based pharmacokinetic (PBPK) model were used to predict the amounts of sulfamethazine residues in edible tissues in swine. A PBPK model for sulfamethazine in swine was adapted to include an oral dosing route. The distributions for sensitive parameters were determined and were used in a Monte Carlo analysis to predict tissue residue times. Validation of the distributions was done by comparison of the results of a Monte Carlo analysis to those obtained with an external data set from the literature and an in vivo pilot study. The model was used to predict the upper limit of the 95% confidence interval of the 99th percentile of the population, as recommended by the U.S. Food and Drug Administration (FDA). The external data set was used to calculate the withdrawal time by using the tolerance limit algorithm designed by FDA. The withdrawal times obtained by both methods were compared to the labeled withdrawal time for the same dose. The Monte Carlo method predicted a withdrawal time of 21 days, based on the amounts of residues in the kidneys. The tolerance limit method applied to the time-limited data set predicted a withdrawal time of 12 days. The existing FDA label withdrawal time is 15 days. PBPK models can incorporate probabilistic modeling techniques that make them useful for prediction of tissue residue times. These models can be used to calculate the parameters required by FDA and explore those conditions where the established withdrawal time may not be sufficient.

FIG. 1.

Schematic diagram of the PBPK model for sulfamethazine in pigs. V, tissue volume; C, tissue concentration; Q, tissue blood flow; Q_tot, cardiac output.

FIG. 2.

Schematic diagram of the oral dosing route of administration.

FIG. 3.

Monte Carlo simulations for sulfamethazine concentrations in edible tissues after intravenous administration. Squares, datum points from the external data set (means from published studies and data for individual pigs from in vivo pilot study) normalized to a dose of 1 mg/kg. (A) Plasma; (B) kidney; (C) liver; (D) muscle; (E) fat.

FIG. 4.

Monte Carlo simulations for sulfamethazine concentration in edible tissues after oral administration. Doses were normalized to a standard dose of 10 mg/kg once daily for 7 days. Squares, datum points from the external data set (means from published studies). (A) Plasma; (B) kidney; (C) liver; (D) muscle; (E) fat.

FIG. 5.

Representative distribution of the time that it takes for sulfamethazine concentrations to fall below the tolerance of 0.1 ppm in kidney tissue from a Monte Carlo run of 1,000 simulations. *, 99th percentile of the distribution; ^, current withdrawal time of 15 days.