Consideration of the applicability domain of an in silico physiologically based pharmacokinetic model for improving the predictivity of food-related compounds.

The increasing demand for non-animal approaches in food safety assessment underscores the need for methods capable of predicting human internal exposure. We systematically evaluated the applicability of a physiologically based pharmacokinetic (PBPK) model-originally developed for pharmaceuticals and general chemicals, to predict physicochemical and pharmacokinetic parameters from chemical structure information and simulate human plasma profiles-to human internal exposure prediction. Food-related compounds were selected from published papers, and human single-dose pharmacokinetic studies were curated when all of the following criteria were met: 1) single administration in humans, 2) dose clearly specified as the target compound amount, 3) unchanged parent compound measured, 4) area under the curve (AUC) analyzed, and 5) no formulation/processing intended to control absorption. Using predicted parameters as PBPK inputs, peak plasma concentration (Cmax) and AUC were simulated and compared with observed values. In the absence of applicability restrictions, prediction ratios (predicted value/observed value) ranged from 0.00970 to 825 for Cmax and from 0.0000299 to 1628 for AUC; 20/36 Cmax and 19/40 AUC data points were within the three-fold error range (0.33-3). Restricting the applicability domain to compounds with predicted intestinal absorption/bioavailability > 0.5 and excluding a specific chemical-space region improved predictivity, with 11/12 (91.6%) Cmax and 9/12 (75.0%) AUC data points within the three-fold error range. Taken together, these results indicate that the in silico PBPK-based approach provides a practical and reasonably accurate estimate of human internal exposure for a subset of food-related compounds when an appropriate applicability domain is defined.