In spite of the extensive use of long-acting beta(2)-agonist (LABA) bronchodilators in asthma, the actual mechanism of their in vivo duration of action is not well understood, primarily due to limitations of standard pharmacokinetic-pharmacodynamic (PKPD) analysis methodologies. We have developed a novel method of analysing lung efficacy vs. time profiles for LABAs that can be used to provide comparative information on the lung PK. We hypothesised that for compounds that do not differ in their PK at the site of PD action, but differ in their in vivo potencies, the relationship between the area under the effect curve (AUEC) and the observed maximum effect (OME) at different doses is described by the same sigmoid curve. We have illustrated this property for standard PKPD models by obtaining analytical solution and through simulations. Anaesthetised dog in vivo effect vs. time profiles were gathered for six inhaled LABA candidates that differ in their in vitro potencies. Neither lung nor systemic PK was available for any compound. Analysis of the AUEC vs. OME data, derived from the efficacy profiles, using nonlinear mixed effects modelling indicated that for four compounds, the observed differences in in vivo duration of action was due to differences in their in vivo potencies and not because of lung PK differences. Therefore, it was concluded that for these compounds, characterisation of lung PK was unlikely to differentiate their PKPD characteristics. Thus, the proposed approach helped focus resources during translational research leading to lead candidate selection.

译文

:尽管在哮喘中广泛使用了长效β(2)-激动剂(LABA)支气管扩张剂,但其体内作用持续时间的实际机制仍未得到很好的了解,这主要是由于标准药代动力学-药效学(PKPD)的局限性)分析方法论。我们已经开发了一种新的分析LABA的时间与时间效率曲线的方法,可用于提供有关肺PK的比较信息。我们假设,对于在PD作用部位的PK不变但体内效力不同的化合物,在不同剂量下效应曲线下的面积(AUEC)与观察到的最大效应(OME)之间的关系用相同的S形曲线描述。我们已经通过获取解析解和仿真来说明了标准PKPD模型的这一特性。收集了六只吸入的LABA候选药物,它们的体外药效不同,麻醉后的狗体内效应与时间的关系曲线。肺和全身性PK均不可用于任何化合物。使用非线性混合效应模型对源自功效谱的AUEC与OME数据进行的分析表明,对于四种化合物,观察到的体内作用持续时间差异是由于其体内效力差异引起的,而不是由于肺部PK差异。因此,可以得出结论,对于这些化合物,肺部PK的表征不太可能区分其PKPD的特征。因此,所提出的方法有助于在翻译研究期间集中资源,从而导致候选者的选择。

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