Use of population pharmacokinetic modeling and Monte Carlo simulation to capture individual animal variability in the prediction of flunixin withdrawal times in cattle

Abstract

The objective of this study was to develop a population pharmacokinetic (PK) model and predict tissue residues and the withdrawal interval (WDI) of flunixin in cattle. Data were pooled from published PK studies in which flunixin was administered through various dosage regimens to diverse populations of cattle. A set of liver data used to establish the regulatory label withdrawal time (WDT) also were used in this study. Compartmental models with first-order absorption and elimination were fitted to plasma and liver concentrations by a population PK modeling approach. Monte Carlo simulations were performed with the population mean and variabilities of PK parameters to predict liver concentrations of flunixin. The PK of flunixin was described best by a 3-compartment model with an extra liver compartment. The WDI estimated in this study with liver data only was the same as the label WDT. However, a longer WDI was estimated when both plasma and liver data were included in the population PK model. This study questions the use of small groups of healthy animals to determine WDTs for drugs intended for administration to large diverse populations. This may warrant a reevaluation of the current procedure for establishing WDT to prevent violative residues of flunixin.

Interspecies Mixed-Effect Pharmacokinetic Modeling of Penicillin G in Cattle and Swine

“…When the label dose is used, a specific residue depletion study in healthy animals is conducted by the sponsor as part of the regulatory approval package. However, the presence of systemic disease or the legal extralabel use of the drug, either via a different route or at a higher dose to treat infections caused by organisms with higher MICs, requires estimation of a prolonged withdrawal interval to ensure that edible products meet food safety guidelines (20,22). In many cases, the label dose of a drug approved decades ago, such as penicillin G, must be increased to effectively treat bacteria with higher MICs without inducing resistance (16).…”

“…Based on the best model for plasma concentrations of penicillin G, tissue compartments, including a liver compartment for cattle, muscle compartment for swine, and kidney compartments for both cattle and swine, subsequently were added. In this modeling process, it was assumed that penicillin was orally administered to the liver compartment directly (20). The final PK structural model developed for blood and tissue concentrations of penicillin is shown in Fig.…”

“…Population pharmacokinetic analysis has been advocated to be used in veterinary medicine for many years (19,20). The development of this technique allows us to explore the relationships between clinical factors (such as weight, age, gender, species, etc.)…”

Tetracycline Residues in Porcine Stomach after Administration via Drinking Water on a Swine Farm

“…PK data were compiled using standard deviations and averages among animals with Excel (Microsoft Corp., Redmond, WA). Two methods for calculating the withdrawal interval (WDI) were incorporated into this study for both weanling and finisher pigs to compare the use of the currently accepted model used by the U.S. Food and Drug Administration (FDA), called the tolerance limit method (2), and a population PK (PopPK) model with Monte Carlo simulation, used by the Food Animal Residue Avoidance Databank (15). In order to establish a withdrawal period using FDA methods, the withdrawal period is determined when the tolerance limit for the tetracycline concentration is at or below the permitted concentration in a specific target tissue (2).…”

Tissue concentrations of sulfamethazine and tetracycline hydrochloride of swine ( Sus scrofa domestica ) as it relates to withdrawal methods for international export

“…The TLM and an alternative population-based statistical pharmacokinetic (PopPK) method were used to determine a safe (with greater than 99% confidence) WDI for TET and SMZ in various tissues based upon US tolerance and European Union (EU) maximum residue limits (MRLs) from the European Medicines Agency standards (EMA, 2014). PopPK has been used in only a few studies to determine safe withdrawal times in food animals species (Martín-Jiménez et al, 2002;Wu et al, 2013); however this method is currently not approved by the FDA as a means of calculating WDI for domestic or international markets. Furthermore, there is currently no standard for how an extended WDI should be calculated or extrapolated from the U.S. FDA TLM.…”