Department of Environmental and Global Health, College of Public Health and Health Professions, University of Florida, Gainesville, Florida 32610, USA.
Center for Environmental and Human Toxicology, University of Florida, Florida 32608, USA.
Toxicol Sci. 2022 Jul 28;188(2):180-197. doi: 10.1093/toxsci/kfac056.
Violative chemical residues in edible tissues from food-producing animals are of global public health concern. Great efforts have been made to develop physiologically based pharmacokinetic (PBPK) models for estimating withdrawal intervals (WDIs) for extralabel prescribed drugs in food animals. Existing models are insufficient to address the food safety concern as these models are either limited to 1 specific drug or difficult to be used by non-modelers. This study aimed to develop a user-friendly generic PBPK platform that can predict tissue residues and estimate WDIs for multiple drugs including flunixin, florfenicol, and penicillin G in cattle and swine. Mechanism-based in silico methods were used to predict tissue/plasma partition coefficients and the models were calibrated and evaluated with pharmacokinetic data from Food Animal Residue Avoidance Databank (FARAD). Results showed that model predictions were, in general, within a 2-fold factor of experimental data for all 3 drugs in both species. Following extralabel administration and respective U.S. FDA-approved tolerances, predicted WDIs for both cattle and swine were close to or slightly longer than FDA-approved label withdrawal times (eg, predicted 8, 28, and 7 days vs labeled 4, 28, and 4 days for flunixin, florfenicol, and penicillin G in cattle, respectively). The final model was converted to a web-based interactive generic PBPK platform. This PBPK platform serves as a user-friendly quantitative tool for real-time predictions of WDIs for flunixin, florfenicol, and penicillin G following FDA-approved label or extralabel use in both cattle and swine, and provides a basis for extrapolating to other drugs and species.
食品动物可食组织中违规化学残留对全球公共卫生构成威胁。人们已投入大量努力开发基于生理学的药代动力学（PBPK）模型，以估算食品动物中超标签规定药物的停药期（WDI）。现有的模型还不足以解决食品安全问题，因为这些模型要么仅限于 1 种特定药物，要么非建模人员难以使用。本研究旨在开发一个用户友好的通用 PBPK 平台，用于预测组织残留并估算牛和猪中氟尼辛、氟苯尼考和青霉素 G 等多种药物的 WDI。基于机制的计算方法用于预测组织/血浆分配系数，并用来自食品动物残留规避数据库（FARAD）的药代动力学数据对模型进行校准和评估。结果表明，对于这 3 种药物，在这 2 种动物中，模型预测值总体上在实验数据的 2 倍以内。在超标签使用和各自美国食品药品监督管理局（FDA）批准的耐受量下，牛和猪的预测 WDI 接近或略长于 FDA 批准的标签停药时间（例如，牛中氟尼辛、氟苯尼考和青霉素 G 的预测 8、28 和 7 天与标签 4、28 和 4 天相比，猪中分别为 28 和 7 天与标签 28 和 4 天相比）。最终模型被转换为基于网络的交互式通用 PBPK 平台。该 PBPK 平台可作为实时预测牛和猪中氟尼辛、氟苯尼考和青霉素 G 的 WDI 的便捷定量工具，可用于 FDA 批准的标签或超标签使用，并为外推至其他药物和物种提供基础。
