Systems Pharmacology Approach for Prediction of Pulmonary and Systemic Pharmacokinetics and Receptor Occupancy of Inhaled Drugs.
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.
Department of Respiratory, Inflammation, and Autoimmunity Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.|School of Engineering, University of Warwick, Coventry, UK.
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Boger
School of Engineering, University of Warwick, Coventry, UK.
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Evans
School of Engineering, University of Warwick, Coventry, UK.
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M
Chappell
Department of Respiratory, Inflammation, and Autoimmunity Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
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Lundqvist
Department of Respiratory, Inflammation, and Autoimmunity Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
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Ewing
Department of Respiratory, Inflammation, and Autoimmunity Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
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Wigenborg
Department of Respiratory, Inflammation, and Autoimmunity Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.|Translational PKPD, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
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Fridén
D000280:Administration, Inhalation; D000818:Animals; D001682:Biological Availability; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D000068298:Fluticasone / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008168:Lung / Q000378:metabolism*; D023421:Models, Animal; D008954:Models, Biological; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
D001993:Bronchodilator Agents; D011965:Receptors, Glucocorticoid; D000068298:Fluticasone