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


  • αCorrection added after online publication <8 November 2012>: <After submitting this manuscript, additional data became available from recent cattle flunixin pharmacokinetic studies in which bioavailabilities for flunixin after IM and SC administration were estimated to be 100%. Since the estimated WDIs for flunixin after extravascular administration routes were sensitive to bioavailability, readers should be mindful that the estimated WDI’s for extravascular administration routes of administration might be similar to that for the IV administration route.>

Jim E. Riviere, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506-5802, USA. E-mail:


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.

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