Bi Goue Denis Gohore, Li Jun, Nekka Fahima
Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada.
Theor Biol Med Model. 2009 Jun 26;6:10. doi: 10.1186/1742-4682-6-10.
Pharmacokinetic and pharmacodynamic (PK/PD) indices are increasingly being used in the microbiological field to assess the efficacy of a dosing regimen. In contrast to methods using MIC, PK/PD-based methods reflect in vivo conditions and are more predictive of efficacy. Unfortunately, they entail the use of one PK-derived value such as AUC or Cmax and may thus lead to biased efficiency information when the variability is large. The aim of the present work was to evaluate the efficacy of a treatment by adjusting classical breakpoint estimation methods to the situation of variable PK profiles.
We propose a logical generalisation of the usual AUC methods by introducing the concept of "efficiency" for a PK profile, which involves the efficacy function as a weight. We formulated these methods for both classes of concentration- and time-dependent antibiotics. Using drug models and in silico approaches, we provide a theoretical basis for characterizing the efficiency of a PK profile under in vivo conditions. We also used the particular case of variable drug intake to assess the effect of the variable PK profiles generated and to analyse the implications for breakpoint estimation.
Compared to traditional methods, our weighted AUC approach gives a more powerful PK/PD link and reveals, through examples, interesting issues about the uniqueness of therapeutic outcome indices and antibiotic resistance problems.
药代动力学和药效学（PK/PD）指标在微生物学领域越来越多地用于评估给药方案的疗效。与使用最低抑菌浓度（MIC）的方法不同，基于PK/PD的方法反映体内情况，并且对疗效更具预测性。不幸的是，它们需要使用一个源自药代动力学的数值，如曲线下面积（AUC）或峰浓度（Cmax），因此当变异性很大时，可能会导致效率信息有偏差。本研究的目的是通过调整经典的断点估计方法以适应药代动力学特征可变的情况，来评估一种治疗方法的疗效。
我们通过引入PK曲线“效率”的概念，对常用的AUC方法进行了合理的推广，其中涉及将疗效函数作为权重。我们针对浓度依赖性和时间依赖性两类抗生素制定了这些方法。使用药物模型和计算机模拟方法，我们为在体内条件下表征PK曲线的效率提供了理论基础。我们还利用药物摄入可变的特殊情况来评估所产生的可变PK曲线的影响，并分析对断点估计的影响。
与传统方法相比，我们的加权AUC方法给出了更强有力的PK/PD联系，并通过实例揭示了关于治疗结果指标的唯一性和抗生素耐药性问题的有趣问题。
