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A geometrical approach to the PKPD modelling of inhaled bronchodilators

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Abstract

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.

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Acknowledgments

The authors thank an anonymous Reviewer whose insightful and detailed comments were instrumental in improving the model and substantially changing the manuscript. This research has been supported by Novartis Pharma AG, Basel, Switzerland.

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Authors and Affiliations

  1. Consiglio Nazionale Delle Ricerche, Istituto di Analisi Dei Sistemi ed Informatica “A. Ruberti”, Viale Manzoni, 30, 00185, Rome, Italy

    Claudio Gaz, Simona Panunzi & Andrea De Gaetano

  2. Unità Funzionale di Pneumologia e Fisiopatologia Respiratoria, Istituto Scientifico Universitario San Raffaele, Milan, Italy

    George Cremona

  3. Novartis Pharmaceutical UK Limited, Wimblehurst Road, West Sussex, RH12 5AB, UK

    Beverley Patterson

Authors
  1. Claudio Gaz
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  2. George Cremona
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  3. Simona Panunzi
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  4. Beverley Patterson
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  5. Andrea De Gaetano
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Correspondence to Andrea De Gaetano.

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Gaz, C., Cremona, G., Panunzi, S. et al. A geometrical approach to the PKPD modelling of inhaled bronchodilators. J Pharmacokinet Pharmacodyn 39, 415–428 (2012). https://doi.org/10.1007/s10928-012-9259-z

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  • DOI: https://doi.org/10.1007/s10928-012-9259-z

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