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A geometrical approach to the PKPD modelling of inhaled bronchodilators

Gaz, Claudio and Cremona, George and Panunzi, Simona and Patterson, Beverley and De Gaetano, Andrea (2012) A geometrical approach to the PKPD modelling of inhaled bronchodilators. Journal of pharmacokinetics and pharmacodynamics, 39 (5). pp. 415-428. ISSN 1567-567X

Abstract

The present work introduces a new method to model the pharmacokinetics and pharmacodynamics (PKPD) of an inhaled dose of bronchodilator. This method provides an alternative approach to classic compartmental representations or computational fluid dynamics.
A five compartment lung model comprising the upper airways, bronchial tree mucosa, bronchial muscles, alveoli and plasma has been modified to take into account anatomical, geometrical features such as bronchial branching and smooth muscle distribution. Many anatomical and physiological features of the bronchial tree depend, as a first approximation, on bronchial generation or on mean distance from the larynx. Among these are diameters, resistances, and receptor density, which work together in determining the local response to the inhaled dose; integrating these local responses over the whole bronchial tree allows an approximation of total broncodilator response, particularly with respect to airflow resistance.
While the PK part of the model reflects classical compartmental assumptions, the PD part substitutes a simplified geometrical and functional description of the bronchial tree for the typical PD models of effect, leading to the direct computation of the approximate FEV1.
In the present work the construction of the model is detailed, and literature data are used to derive the anatomical approximations used. Simulation of two asthmatic subjects is employed to illustrate the behaviour of the model in representing the evolution over time of the distribution and effect of an inhaled dose of bronchodilator. The relevance of formulation diffusivity on therapeutic efficacy is discussed and conclusions regarding the applicability of the model in interpreting single-subject and population experiments are drawn.

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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2705

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