Tissue Distribution and Pharmacokinetic Characteristics of Aztreonam Based on Multi-Species PBPK Model

<b>Background/Objectives</b>: As a monocyclic β-lactam antibiotic, aztreonam has regained attention recently because combining it with β-lactamase inhibitors helps fight drug-resistant bacteria. This study aimed to systematically characterize the plasma and tissue concentration-time profiles of aztreonam in rats, mice, dogs, monkeys, and humans by developing a multi-species, physiologically based pharmacokinetic (PBPK) model. <b>Methods</b>: A rat PBPK model was optimized and validated using plasma concentration-time curves determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) following intravenous administration, with reliability confirmed through another dose experiment. The rat model characteristics, modeling experience, ADMET Predictor (11.0) software prediction results, and allometric scaling were used to extrapolate to mouse, human, dog, and monkey models. The tissue-to-plasma partition coefficients (<i>K_p</i> values) were predicted using GastroPlus (9.0) software, and the sensitivity analyses of key parameters were evaluated. Finally, the cross-species validation was performed using the average fold error (AFE) and absolute relative error (ARE). <b>Results</b>: The cross-species validation showed that the model predictions were highly consistent with the experimental data (AFE < 2, ARE < 30%), but the deviation of the volume of distribution (<i>V_ss</i>) in dogs and monkeys suggested the need to supplement the species-specific parameters to optimize the prediction accuracy. The <i>K_p</i> values revealed a high distribution of aztreonam in the kidneys (<i>K_p</i> = 2.0-3.0), which was consistent with its clearance mechanism dominated by renal excretion. <b>Conclusions</b>: The PBPK model developed in this study can be used to predict aztreonam pharmacokinetics across species, elucidating its renal-targeted distribution and providing key theoretical support for the clinical dose optimization of aztreonam, the assessment of target tissue exposure in drug-resistant bacterial infections, and the development of combination therapy strategies.