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首页> 外文期刊>The Journal of Antimicrobial Chemotherapy >A combined in vivo pharmacokinetic-in vitro pharmacodynamic approach to simulate target site pharmacodynamics of antibiotics in humans.
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A combined in vivo pharmacokinetic-in vitro pharmacodynamic approach to simulate target site pharmacodynamics of antibiotics in humans.

机译：一种组合的体内药代动力学-体外药效学方法，可模拟人体中抗生素的目标部位药效学。

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摘要

We describe a new approach to quantify in vivo anti-infective activity by simulating effect site pharmacokinetics of antibiotics in vitro. This approach is based on (i) the in vivo measurement of interstitial drug pharmacokinetics (PK) at the target site and (ii) a subsequent pharmacodynamic (PD) simulation of the time versus drug concentration profile in an in vitro setting. To demonstrate the feasibility of this approach, individual time-concentration profiles of ciprofloxacin were measured in the interstitial space fluid of eight healthy volunteers by microdialysis following iv administration of 200 mg. Thereafter, different isolates of Pseudomonas aeruginosa were exposed in vitro to the interstitial ciprofloxacin concentration profile obtained from in vivo experiments. This led to a 1- to 3-log10 decrease in the number of viable organisms after 8 h. Significant correlations were observed between the maximal bactericidal effect and several PK surrogate parameters, notably the AUC/MIC ratio (P: = 0.0005), the C:max/MIC ratio (P: = 0.006) and the time > MIC (P: = 0.02). Furthermore, the data were analysed with an integrated PK-PD model allowing a much more detailed evaluation of the data than using MIC. The model employed an E:max relationship to link unbound ciprofloxacin concentration to bacterial kill rate. In conclusion, our experiments show that therapeutic success and failure in antimicrobial therapy may be explained by pharmacokinetic variability at the target site. Therefore, the in vivo PK-in vitro PD approach presented in our study may provide valuable guidance for drug and dose selection of antimicrobial agents.
机译：我们描述了一种通过模拟抗生素在体外的作用部位药代动力学来量化体内抗感染活性的新方法。该方法基于（i）在靶位点的间质药物药代动力学（PK）的体内测量，以及（ii）在体外环境中时间对药物浓度曲线的后续药效学（PD）模拟。为了证明这种方法的可行性，在静脉注射200 mg后，通过微透析在八名健康志愿者的间质液中测量了环丙沙星的时间浓度分布。此后，将铜绿假单胞菌的不同分离物体外暴露于从体内实验获得的间质环丙沙星浓度曲线。这导致8小时后活菌数量减少了1-log10。在最大杀菌效果和几个PK替代参数之间观察到显着相关性，特别是AUC / MIC比（P：= 0.0005），C：max / MIC比（P：= 0.006）和时间> MIC（P：= 0.02）。此外，使用集成的PK-PD模型分析数据，与使用MIC相比，可以对数据进行更详细的评估。该模型采用E：max关系将未结合的环丙沙星浓度与细菌杀灭率联系起来。总之，我们的实验表明，抗微生物治疗的成功与失败可以通过靶点药代动力学的变化来解释。因此，在我们的研究中提出的体内PK体外PD方法可能为抗菌药物的药物和剂量选择提供有价值的指导。

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