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Integration of Food Animal Residue Avoidance Databank (FARAD) empirical methods for drug withdrawal interval determination with a mechanistic population-based interactive physiologically based pharmacokinetic (iPBPK) modeling platform: example for flunixin meglumine administration

  • Toxicokinetics and Metabolism
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Abstract

Violative chemical residues in animal-derived food products affect food safety globally and have impact on the trade of international agricultural products. The Food Animal Residue Avoidance Databank program has been developing scientific tools to provide appropriate withdrawal interval (WDI) estimations after extralabel drug use in food animals for the past three decades. One of the tools is physiologically based pharmacokinetic (PBPK) modeling, which is a mechanistic-based approach that can be used to predict tissue residues and WDIs. However, PBPK models are complicated and difficult to use by non-modelers. Therefore, a user-friendly PBPK modeling framework is needed to move this field forward. Flunixin was one of the top five violative drug residues identified in the United States from 2010 to 2016. The objective of this study was to establish a web-based user-friendly framework for the development of new PBPK models for drugs administered to food animals. Specifically, a new PBPK model for both cattle and swine after administration of flunixin meglumine was developed. Population analysis using Monte Carlo simulations was incorporated into the model to predict WDIs following extralabel administration of flunixin meglumine. The population PBPK model was converted to a web-based interactive PBPK (iPBPK) framework to facilitate its application. This iPBPK framework serves as a proof-of-concept for further improvements in the future and it can be applied to develop new models for other drugs in other food animal species, thereby facilitating the application of PBPK modeling in WDI estimation and food safety assessment.

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Acknowledgements

The authors would like to acknowledge the help from Mal Hoover, the medical illustrator affiliated with College of Veterinary Medicine of Kansas State University, for creating Fig. 1. This work was supported by the United States Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA) for the Food Animal Residue Avoidance Databank (FARAD) Program (Award No. 2015-41480-23972, 2016-41480-25729, 2017-41480-27310, and 2018-41480-28805).

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  1. Institute of Computational Comparative Medicine (ICCM), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, 66506, USA

    Miao Li, Yi-Hsien Cheng, Jim E. Riviere & Zhoumeng Lin

  2. Center for Chemical Toxicology Research and Pharmacokinetics, Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27606, USA

    Jason T. Chittenden, Ronald E. Baynes & Jim E. Riviere

  3. Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616, USA

    Lisa A. Tell

  4. Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, 24060, USA

    Jennifer L. Davis

  5. Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32610, USA

    Thomas W. Vickroy

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Li, M., Cheng, YH., Chittenden, J.T. et al. Integration of Food Animal Residue Avoidance Databank (FARAD) empirical methods for drug withdrawal interval determination with a mechanistic population-based interactive physiologically based pharmacokinetic (iPBPK) modeling platform: example for flunixin meglumine administration. Arch Toxicol 93, 1865–1880 (2019). https://doi.org/10.1007/s00204-019-02464-z

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