Preclinical Experimental and Mathematical Approaches for Assessing Effective Doses of Inhaled Drugs, Using Mometasone to Support Human Dose Predictions

Caniga, Michael; Cabal, Antonio; Mehta, Khamir; Ross, David S.; Gil, Malgorzata A; Woodhouse, Janice D; Eckman, Joseph; Naber, John R.; Callahan, Marissa K; Goncalves, Luciano; Hill, Susan E.; McLeod, Robbie L.; McIntosh, Fraser; Freke, Mark C; Visser, Sandra A.G.; Johnson, Neil; Salmon, M; Cicmil, Milenko

doi:10.1089/jamp.2015.1253

Cited by 18 publications

(20 citation statements)

References 36 publications

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“…In order to provide a predictive platform to describe both the pharmacokinetics in the lung, and the subsequent pharmacodynamic effects, Caniga et al . developed an experimental inhalation platform that consists of an animal model coupled with a mathematical model to describe the drug dissolution, transport, distribution, and efficacy following inhaled delivery of mometasone in both rodents and humans . This work provides a novel platform that can be expanded to estimate drug penetration following inhaled delivery and subsequent PD effects for other inhaled corticosteroids.…”

Section: Lungmentioning

confidence: 99%

Importance of Drug Pharmacokinetics at the Site of Action

Zou

Savić

et al. 2017

Clinical Translational Sci

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Section: Lungmentioning

confidence: 99%

Importance of Drug Pharmacokinetics at the Site of Action

Zou

Savić

et al. 2017

Clinical Translational Sci

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“…Currently, there exist several different inhalation physiologically based pharmacokinetic (PBPK) models, each of which covers some but not all of these important phenomena. [9][10][11][12][13] To model the regionally varying concentrations, expected due to, for example, the deposition pattern, MCC, and the heterogeneous physiology, a high spatial resolution is required. Although models discretized into as few as two (tracheobronchial and alveolar) 9,11 or three pulmonary compartments (thoracic, bronchiolar, and alveolar) 13 have contributed to our understanding of inhaled drug disposition, their limited spatial resolution significantly affects the simulated result.…”

Section: Wwwpsp-journalcommentioning

confidence: 99%

“…[9][10][11][12][13] To model the regionally varying concentrations, expected due to, for example, the deposition pattern, MCC, and the heterogeneous physiology, a high spatial resolution is required. Although models discretized into as few as two (tracheobronchial and alveolar) 9,11 or three pulmonary compartments (thoracic, bronchiolar, and alveolar) 13 have contributed to our understanding of inhaled drug disposition, their limited spatial resolution significantly affects the simulated result. Physiology and deposition vary richly across the lungs, and averaging these fail to capture important nonlinear phenomena, as conclusions from a lumped region are not necessarily valid across the entire space.…”

Section: Wwwpsp-journalcommentioning

confidence: 99%

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A Partial Differential Equation Approach to Inhalation Physiologically Based Pharmacokinetic Modeling

Boger

Wigström

2018

CPT Pharmacom & Syst Pharma

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The heterogeneous nature of the lungs and the range of processes affecting pulmonary drug disposition make prediction of inhaled drugs challenging. These predictions are critical, as the local exposure cannot be measured and current inhalation physiologically based pharmacokinetic (PBPK) models do not capture all necessary features. Utilizing partial differential equations, we present an inhalation PBPK model to describe the heterogeneity in both lung physiology and particle size. The model mechanistically describes important processes, such as deposition, mucociliary clearance, and dissolution. In addition, simplifications are introduced to reduce computational cost without loss of accuracy. Three case studies exemplify how the model can enhance our understanding of pulmonary drug disposition. Specific findings include that most small airways can be targeted by inhalation, and overdosing may eradicate the advantage of inhalation. The presented model can guide the design of inhaled molecules, formulations, as well as clinical trials, providing opportunities to explore regional targeting.

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“…Physiologically based pharmacokinetic modeling also bears promise for scaling inhalation PK from animals to man. 33,34…”

Section: Precision-cut Lung Slices For Profiling Of Inhaled Compoundsmentioning

confidence: 99%

Current Progress Toward a Better Understanding of Drug Disposition Within the Lungs: Summary Proceedings of the First Workshop on Drug Transporters in the Lungs

Ehrhardt

Bäckman

Couet

et al. 2017

Journal of Pharmaceutical Sciences

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The School of Pharmacy and Pharmaceutical Sciences at Trinity College Dublin hosted the "1 Workshop on Drug Transporters in the Lungs" in September 2016 to discuss the impact of transporters on pulmonary drug disposition and their roles as drug targets in lung disease. The workshop brought together about 30 scientists from academia and pharmaceutical industry from Europe and Japan and addressed the primary questions: What do we know today, and what do we need to know tomorrow about transporters in the lung? The 3 themes of the workshop were: (1) techniques to study drug transporter expression and actions in the lungs; (2) drug transporter effects on pulmonary pharmacokinetics-case studies; and (3) transporters as drug targets in lung disease. Some of the conclusions of the workshop were: suitable experimental models that allow studies of transporter effects are available; data from these models convincingly show a contribution of both uptake and efflux transporters on pulmonary drug disposition; the effects of transporters on drug lung PK is now better conceptualized; some transporters are associated with lung diseases. However, more work is needed to establish which of the available models best translate to the clinical situation.

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Preclinical Experimental and Mathematical Approaches for Assessing Effective Doses of Inhaled Drugs, Using Mometasone to Support Human Dose Predictions

Abstract: Presently, we report on a novel and sophisticated mathematical model leading to improvements in a current inhaled drug development practices by providing a quantitative understanding of the relationship between PD effects and drug concentration in lungs.

Cited by 18 publications

References 36 publications

Importance of Drug Pharmacokinetics at the Site of Action

Importance of Drug Pharmacokinetics at the Site of Action

A Partial Differential Equation Approach to Inhalation Physiologically Based Pharmacokinetic Modeling

Current Progress Toward a Better Understanding of Drug Disposition Within the Lungs: Summary Proceedings of the First Workshop on Drug Transporters in the Lungs

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