基于流速调节技术的喹诺酮类抗菌药体外PK/PD模拟研究

As a drug class with wide antimicrobial spectrum and low risk of adverse effects, quinolones have been acknowledged as the first-choice agents for the treatment of respiratory infection and urinary tract infections. However, under the selective pressure from the extensive use of quinolones, the population of drug resistant strains have grown remarkably in recent years. This could be shown as the appearance of quinolone-resistant Streptococcus pneumoniae and the resistant strains of Staphylococcus aureus. Hence, it is quite essential to perform the rational use of antimicrobials, and to search for new compounds with favourable antibacterial activities against multiple bacteria with drug-resistance. The aim of this project is to take nemonoxacin, a novel nonfluorinated quinolone, as an investigational drug, and to establish an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model to analyze the relationship of PK of nemonoxacin and its antibacterial activity against Streptococcus pneumoniae. A mathematical model is developed to illustrate the relationship between the drug resistance of Streptococcus pneumoniae and the exposure of nemonoxacin. Monte Carlo simulation of PK/PD model is also employed to provide basis for determing reasonable dosing regimen of nemonoxacin in clinic. Considering the fact that the simulation of different PK model in vivo could lead to various structure of PK model in vitro, a technology of flow rate modulation is proposed in this study. This could meet the requirements of accurate PK simulation and simplification of in vitro experimental settings simultaneously. The ultimate objective of this project tries to bring some technological innovation for the PK/PD study in vitro, and to provide novel evaluation measures for the rational use of antimicrobials.

喹诺酮类抗菌药是具有较广抗菌谱、不良反应风险较低的药物，是治疗呼吸道感染和尿路感染的首选药。随着该类药物广泛运用造成的选择性压力，耐药菌株显著增多，表现为喹诺酮类耐药肺炎链球菌和金黄色葡萄球菌耐药株的出现。因此，实施抗菌药物合理应用，并寻找对多种耐药菌具有良好抗菌活性的新型化合物很有必要。本项目以无氟喹诺酮类新药奈诺沙星为研究对象，以肺炎链球菌作为考察细菌，建立体外药动学/药效学(PK/PD)模型探讨该药PK和PD之间的关系，构建PK/PD数学模型阐述细菌耐药性消长与药物暴露之间的关联规律，通过蒙特卡洛模拟研究为临床给药方案制订提供合理依据。针对不同抗菌药物药动学模型形式不同导致体外PK模型结构难以统一的不利因素，本项目提出流速动态调节技术，同时满足体外PK精确模拟和简化模型装置的要求。通过本项目研究，力争在抗菌药物体外PK/PD研究方法上有所创新，为抗菌药物合理应用提供新的定量评价手段。

抗菌药物体外PK/PD模型是借助体外装置同时模拟抗菌药物体内过程及药效学变化的研究技术。目前的体外PK模拟仅限于一室和二室模型体外模拟，模拟二室模型时还存在装置复杂导致操作性不佳等问题。为解决该问题，本研究提出了流速调节技术，实现了体外一室模型装置准确模拟静注、静滴或口服给药后的药动学(包括单剂或多剂)，对线性药动学模型(如一室、二室和三室模型)以及非线性药动学模型体外模拟均适用。以喹诺酮类抗菌新药奈诺沙星为研究对象，应用该技术开展了针对肺炎链球菌的体外PK/PD研究。实验结果证明该药对敏感细菌具有浓度依赖性，而对于耐药细菌呈现时间依赖性的杀菌作用特点，此与PK/PD数学模型分析结果相吻合。同时，本项目还将流速调节技术拓展应用于其它类型抗菌药物(如左奥硝唑和美罗培南)体外PK/PD研究。由于临床上倡导通过联合用药来减少细菌耐药，本项目探索进行了体外联合用药PK/PD模拟的流速调节技术研究。本研究为拓宽抗菌药物体外PK/PD模拟范围提供了新的思路，且为体外联合用药PK/PD模型平台的搭建初步奠定了基础。