A generic physiologically based kinetic model for the domestic cat (Felis catus): Model characterisation, validation...

Domestic cats (Felis catus) are among the most popular pets in the world, with the global domestic cat population generally estimated to exceed 600 million and potentially approach 1 billion when feral populations are included. As hypercarnivores, cats exhibit unique metabolic deficiencies, particularly in phase II conjugation enzymes (e.g., glucuronidation, glycine conjugation), which impair elimination of phenolic xenobiotics including pharmaceuticals, feed additives, and contaminants. Consequently, the European Food Safety Authority (EFSA) Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) recommends an additional default uncertainty factor (UF) of 5 for such compounds. Physiologically based kinetic (PBK) modelling offers a mechanistic approach to refine these default factors using chemical-specific kinetic data and such models for the domestic cat are not currently available to the scientific and risk assessment community. Hence, this manuscript focuses on the development and validation of a generic PBK model for the species Felis catus according to the six-step process from the template of the Organisation for Economic Cooperation and Development (OECD) guidance document on characterisation, validation and reporting of PBK models for regulatory purposes. The model integrates meta-analysed physiological parameters from the peer-reviewed literature and 11 perfusion limited compartments. The model has been validated using chemical-specific inputs for 15 pharmaceuticals using in vitro and in vivo clearances to compare in vivo to in vivo and in vitro to in vivo predictions with the available experimental data for plasma maximum concentration (Cmax) and area-under-the-curve (AUC) values in blood after oral and intravenous exposure. Impact of bioavailability on model performance has also been assessed using conservative default values and reported or estimated values. In addition, global sensitivity analysis using the Sobol method identified the muscle:blood partition coefficient as the dominant parameter influencing model output variance. Overall, the generic PBK cat model performed well and most predictions accounting for bioavailability using in vitro derived clearance yielded 86% of Cmax predictions and 64% of AUC predictions were within 2-3-fold of the experimental data as recommended by the OECD. Future applications and refinements of the model with regard to NGRA of food and feed chemicals are highlighted.