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Model-based drug development in pulmonary delivery: pharmacokinetic analysis of novel drug candidates for treatment of Pseudomonas aeruginosa lung infection

Sou, Tomás; Kukavica-Ibrulj, Irena; Soukarieh, Fadi; Halliday, Nigel; Levesque, Roger C.; Williams, Paul; Stocks, Michael; Cámara, Miguel; Friberg, Lena E.; Bergström, Christel A.S.

Authors

Tomás Sou

Irena Kukavica-Ibrulj

Nigel Halliday

Roger C. Levesque

PAUL WILLIAMS paul.williams@nottingham.ac.uk
Professor of Molecular Microbiology

MICHAEL STOCKS MICHAEL.STOCKS@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistryand Drug Discovery

Lena E. Friberg

Christel A.S. Bergström



Abstract

Antibiotic resistance is a major public health threat worldwide. In particular, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. We are therefore developing a novel class of anti-virulence agents, quorum sensing inhibitors (QSIs), which inhibit biofilm formation and sensitise PA to antibiotic treatments. For respiratory conditions, targeted delivery to the lung could achieve higher local concentrations with reduced risk of adverse systemic events. In this study, we report the pharmacokinetics of three prototype QSIs after pulmonary delivery, and the simultaneous analysis of the drug concentration-time profiles from bronchoalveolar lavage, lung homogenate and plasma samples, using a modelling approach. In addition to facilitating the direct comparison and selection of drug candidates, the developed model was used for dosing simulation studies to predict in vivo exposure following different dosing scenarios. The results suggest that systemic clearance has limited impact on local drug exposure in the lung after pulmonary delivery. Therefore, we believe that novel QSIs designed for pulmonary delivery as targeted treatment for respiratory conditions should ideally have a long residence time in the lung for local efficacy with rapid clearance after systemic absorption for reduced risk of adverse systemic events.

Citation

Sou, T., Kukavica-Ibrulj, I., Soukarieh, F., Halliday, N., Levesque, R. C., Williams, P., …Bergström, C. A. (2019). Model-based drug development in pulmonary delivery: pharmacokinetic analysis of novel drug candidates for treatment of Pseudomonas aeruginosa lung infection. Journal of Pharmaceutical Sciences, 108(1), 630-640. https://doi.org/10.1016/j.xphs.2018.09.017

Journal Article Type Article
Acceptance Date Sep 17, 2018
Online Publication Date Sep 23, 2018
Publication Date 2019-01
Deposit Date Oct 2, 2018
Publicly Available Date Jan 9, 2019
Journal Journal of Pharmaceutical Sciences
Print ISSN 0022-3549
Electronic ISSN 1520-6017
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 108
Issue 1
Pages 630-640
DOI https://doi.org/10.1016/j.xphs.2018.09.017
Keywords pulmonary drug delivery; pharmacometrics; PK/PD modeling; preclinical pharmacokinetics;absorption; solubility; metabolic clearance; distribution; disposition; simulations
Public URL https://nottingham-repository.worktribe.com/output/1142576
Publisher URL https://www.sciencedirect.com/science/article/pii/S0022354918305446

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Model-Based Drug Development in Pulmonary Delivery: Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection (1.7 Mb)
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Publisher Licence URL
http://creativecommons.org/licenses/by-nc-nd/4.0/





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