Ye Xiao, Sun Xiaolong, Zhang Jianing, Yu Min, Wen Nie, Geng Xingchao, Liu Ying
Institute for Safety Evaluation, National Institutes for Food and Drug Control, Beijing Key Laboratory for Safety Evaluation of Drugs, Beijing 100176, China.
Pharmaceutics. 2025 Jun 6;17(6):748. doi: 10.3390/pharmaceutics17060748.
: 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. : 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 ( 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). : 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 () in dogs and monkeys suggested the need to supplement the species-specific parameters to optimize the prediction accuracy. The values revealed a high distribution of aztreonam in the kidneys ( = 2.0-3.0), which was consistent with its clearance mechanism dominated by renal excretion. : 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.
作为一种单环β-内酰胺抗生素，氨曲南最近重新受到关注，因为将其与β-内酰胺酶抑制剂联合使用有助于对抗耐药菌。本研究旨在通过建立一个多物种、基于生理的药代动力学（PBPK）模型，系统地表征氨曲南在大鼠、小鼠、犬、猴和人类体内的血浆和组织浓度-时间曲线。：使用液相色谱-串联质谱（LC-MS/MS）测定静脉给药后血浆浓度-时间曲线，对大鼠PBPK模型进行优化和验证，并通过另一剂量实验确认其可靠性。利用大鼠模型特征、建模经验、ADMET Predictor（11.0）软件预测结果和异速缩放法外推至小鼠、人类、犬和猴模型。使用GastroPlus（9.0）软件预测组织-血浆分配系数（值），并评估关键参数的敏感性分析。最后，使用平均倍数误差（AFE）和绝对相对误差（ARE）进行跨物种验证。：跨物种验证表明，模型预测与实验数据高度一致（AFE < 2，ARE < 30%），但犬和猴体内分布容积（）的偏差表明需要补充物种特异性参数以优化预测准确性。值显示氨曲南在肾脏中的分布较高（ = 2.0 - 3.0），这与其以肾排泄为主的清除机制一致。：本研究建立的PBPK模型可用于预测氨曲南在不同物种中的药代动力学，阐明其肾脏靶向分布，并为氨曲南的临床剂量优化、耐药菌感染中靶组织暴露评估及联合治疗策略的制定提供关键理论支持。
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