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Systems pharmacology approach for prediction of pulmonary and systemic pharmacokinetics and receptor occupancy of inhaled drugs
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Boger, Elin, Evans, Neil D., Chappell, M. J. (Michael J.), Lundqvist, A., Ewing, P., Wigenborg, A. and Friden, M. (2016) Systems pharmacology approach for prediction of pulmonary and systemic pharmacokinetics and receptor occupancy of inhaled drugs. CPT : Pharmacometrics & Systems Pharmacology, 5 (4). pp. 201-210. doi:10.1002/psp4.12074 ISSN 2163-8306.
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Official URL: http://dx.doi.org/10.1002/psp4.12074
Abstract
Pulmonary drug disposition after inhalation is complex involving mechanisms, such as regional drug deposition, dissolution, and mucociliary clearance. This study aimed to develop a systems pharmacology approach to mechanistically describe lung disposition in rats and thereby provide an integrated understanding of the system. When drug- and formulation-specific properties for the poorly soluble drug fluticasone propionate were fed into the model, it proved predictive of the pharmacokinetics and receptor occupancy after intravenous administration and nose-only inhalation. As the model clearly distinguishes among drug-specific, formulation-specific, and system-specific properties, it was possible to identify key determinants of pulmonary selectivity of receptor occupancy of inhaled drugs: slow particle dissolution and slow drug-receptor dissociation. Hence, it enables assessment of factors for lung targeting, including molecular properties, formulation, as well as the physiology of the animal species, thereby providing a general framework for rational drug design and facilitated translation of lung targeting from animal to man.
Item Type: | Journal Article | ||||||||||
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Subjects: | Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology |
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Divisions: | Faculty of Science, Engineering and Medicine > Engineering > Engineering | ||||||||||
Library of Congress Subject Headings (LCSH): | Pharmacology -- mathematical models, Lungs , Rats, Physiology | ||||||||||
Journal or Publication Title: | CPT : Pharmacometrics & Systems Pharmacology | ||||||||||
Publisher: | John Wiley & Sons, Inc. | ||||||||||
ISSN: | 2163-8306 | ||||||||||
Official Date: | 27 April 2016 | ||||||||||
Dates: |
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Volume: | 5 | ||||||||||
Number: | 4 | ||||||||||
Page Range: | pp. 201-210 | ||||||||||
DOI: | 10.1002/psp4.12074 | ||||||||||
Status: | Peer Reviewed | ||||||||||
Publication Status: | Published | ||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||
Date of first compliant deposit: | 5 September 2016 | ||||||||||
Date of first compliant Open Access: | 5 September 2016 | ||||||||||
Funder: | Seventh Framework Programme (European Commission) (FP7) | ||||||||||
Grant number: | Project No. 316736 and Innovative Modelling for Pharmacological Advances through Collaborative Training (IMPACT), (FP7) |
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