关键词: 药动学, 药效学, 抗菌素, 体外动力学模型, 动物模型, 蒙地卡罗模拟

Abstract: There is a pressing need for new antibacterial agents due to the development of drug-resistant pathogens.Unfortunately drug development is a difficult and complicated process.The traditional approach in searching for a right dose is quite empirical, both costly and time-consuming.To enhance the ability to predict the likelihood of success for lead compound selection, in vitro pharmacodynamic and in vivo animal infection models are now extensively used.The value of these pre-clinical experiments, combined with mathematical modeling, helps to identify a pharmacokinetic (PK) -pharmacodynamic (PD) exposure measure which best predicts the therapeutic efficacy, and to quantify the magnitude of this index required for in vivo efficacy.PK-PD target attainment analyses using Monte Carlo simulation to integrate interpatient variability in drug exposure (PK), drug potency (MIC), and in vivo exposure targets that are predictive of positive therapeutic outcomes are influencing antibacterial drug development for proof of concept, for dose and dosing interval selection, for determining susceptibility breakpoints, and for evaluating the clinical meaning of antibacterial resistance.In this article, the key concepts of antibacterial PK-PD and model based antibacterial drug development strategy and process are critically reviewed.

Key words: pharmacokinetics, pharmacodynamics, antibacterial, in vitro model, animal models, Monte Carlo simulation, model based drug development