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Systems Pharmacology Approach for Prediction of Pulmonary and Systemic Pharmacokinetics and Receptor Occupancy of Inhaled Drugs
AstraZeneca R&D, Dept Resp Inflammat & Autoimmun Innovat Med, Molndal, Sweden.;Univ Warwick, Sch Engn, Coventry, W Midlands, England..
Univ Warwick, Sch Engn, Coventry, W Midlands, England..
Univ Warwick, Sch Engn, Coventry, W Midlands, England..
AstraZeneca R&D, Dept Resp Inflammat & Autoimmun Innovat Med, Molndal, Sweden..
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2016 (English)In: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 5, no 4, 201-210 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 5, no 4, 201-210 p.
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Pharmacology and Toxicology
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URN: urn:nbn:se:uu:diva-303401DOI: 10.1002/psp4.12074ISI: 000381564500005PubMedID: 27104089OAI: oai:DiVA.org:uu-303401DiVA: diva2:971762
Available from: 2016-09-19 Created: 2016-09-19 Last updated: 2016-09-19Bibliographically approved

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Fridén, Markus
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Department of Pharmaceutical Biosciences
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