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Lung-targeted receptor occupancy by drug inhalation : an experimental and computational evaluation.
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Boger, Elin (2016) Lung-targeted receptor occupancy by drug inhalation : an experimental and computational evaluation. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3065381~S15
Abstract
Inhalation is attractive for treating respiratory diseases since it offers an opportunity to achieve lung-selectivity, i.e. high local and low systemic levels of unbound drug. Nevertheless, evaluation and prediction of the former is challenging for reasons including: 1) the unbound blood concentration cannot be assumed to reflect the free lung target site exposure after inhalation, 2) it is not possible directly measure unbound drug concentrations locally in the lung, and 3) pulmonary drug disposition is known to be a complex interplay between numerous processes. This thesis therefore aims to increase the understanding of how different drug- and formulation-specific properties relate to the free target site exposure to inhaled drug. This was done by: 1) developing and subsequently applying an experimental methodology for measuring pulmonary and systemic occupancy of a receptor targeted by inhaled drugs, and 2) developing a rat physiologically-based pharmacokinetic (PBPK) model, which mechanistically describes underlying processes of pulmonary drug disposition. Experimental studies provided data on the time-course of the PK and receptor occupancy after intravenous (IV) and inhaled drug delivery of fluticasone propionate (FP). The binding kinetics parameters, which were estimated from data generated after IV-dosing, were used as input parameters to the developed model together with other properties specific to FP. The model accurately described the PK and receptor binding for several IV-doses. Predictions were consistent with the observations from inhalation studies, confirming that FP has a dissolution rate-limited absorption and highlighting that drug in solid state does not contribute to receptor binding. As the model is mechanistic, it can assess how different drug- and formulation-specific properties, or combinations thereof, give rise to lung-selectivity.
Specific findings include lung-selectivity possibly being unattainable in well-perfused lung regions and that slow drug-receptor dissociation can provide lung-selectivity. Hence, the model lends itself to guiding the design of inhaled compounds and formulations.
Item Type: | Thesis (PhD) | ||||
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Subjects: | R Medicine > RC Internal medicine | ||||
Library of Congress Subject Headings (LCSH): | Respiratory therapy, Respiratory organs -- Diseases -- Treatment, Lungs -- Diseases, Drugs -- Administration | ||||
Official Date: | May 2016 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | School of Engineering | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | FrideĢn, Markus ; Chappell, Michael John, 1960- ; Evans, Neil | ||||
Sponsors: | European Commission | ||||
Format of File: | |||||
Extent: | xxi, 307 leaves : illustrations, charts. | ||||
Language: | eng |
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