A geometrical approach to the PKPD modelling of inhaled bronchodilators
A geometrical approach to the PKPD modelling of inhaled bronchodilators
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DOI：
10.1007/s10928-012-9259-z
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发表时间：
2012-10-01
影响因子：
2.5
通讯作者：
De Gaetano, Andrea
中科院分区：
文献类型：
--
作者：
Gaz, Claudio;Cremona, George;De Gaetano, Andrea
本工作介绍了一种新的方法来模拟吸入剂量的支气管扩张剂的药代动力学（PK）和药效学（PD），替代经典的区室表征或计算流体动力学。一个包括消化道吸收（肠道）、支气管树粘膜、支气管肌肉、血浆和消除/排泄途径的五室PK模型已经被开发出来。支气管树的许多解剖和生理特征取决于支气管的产生或与喉部的平均距离。其中包括直径、耐药性和受体密度，它们共同决定了吸入药物的局部反应；在整个支气管树上对这些局部反应进行积分，可以近似地得到支气管扩张剂的总反应和气流阻力。该模型的PK部分反映了经典的区室假设，而PD部分将支气管树的简化几何和功能描述添加到支气管肌肉局部作用的典型经验模型中，从而直接计算1 s内的近似用力呼气体积（FEV1）。本文在参考文献数据的基础上，对模型的构建进行了详细的阐述。模拟一个假设的哮喘受试者被用来说明模型的行为，以代表随时间的演变分布和吸入剂量的支气管扩张剂的药理学作用。讨论了颗粒大小和药物配方扩散率与治疗效果的相关性。
The present work introduces a new method to model the pharmacokinetics (PK) and pharmacodynamics (PD) of an inhaled dose of bronchodilator, alternative to classic compartmental representations or computational fluid dynamics. A five compartment PK model comprising alimentary tract absorption (gut), bronchial tree mucosa, bronchial muscles, plasma, and elimination/excretion pathways has been developed. Many anatomical and physiological features of the bronchial tree depend on bronchial generation or on mean distance from the larynx. Among these are diameters, resistances, and receptor density, which determine together the local response to the inhaled drug; integrating these local responses over the whole bronchial tree allows an approximation of total bronchodilator response and airflow resistance. While the PK part of the model reflects classical compartmental assumptions, the PD part adds a simplified geometrical and functional description of the bronchial tree to a typical empirical model of local effect on bronchial muscle, leading to the direct computation of the approximate forced expiratory volume in 1 s (FEV1). In the present work the construction of the model is detailed, with reference to literature data. Simulation of a hypothetical asthmatic subject is employed to illustrate the behaviour of the model in representing the evolution over time of the distribution and pharmacological effect of an inhaled dose of a bronchodilator. The relevance of particle size and drug formulation diffusivity on therapeutic efficacy is discussed.