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- Title
Systems Pharmacology Approach for Prediction of Pulmonary and Systemic Pharmacokinetics and Receptor Occupancy of Inhaled Drugs.
- Authors
Boger, E; Evans, N; Chappell, M; Lundqvist, A; Ewing, P; Wigenborg, A; Fridén, M
- 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.
- Subjects
RESPIRATORY therapy; FLUTICASONE propionate; PHARMACOKINETICS; REGIONAL chemotherapy; PHARMACEUTICAL research; LABORATORY rats; DRUG design; THERAPEUTICS
- Publication
CPT: Pharmacometrics & Systems Pharmacology, 2016, Vol 5, Issue 4, p201
- ISSN
2163-8306
- Publication type
Article
- DOI
10.1002/psp4.12074