A number of inhaled medications used to treat respiratory diseases (such as asthma and COPD) will soon be candidates for generic drugs due to the expiration of existing patents. If these drugs can be offered as generics, reduced costs may be possible while maintaining safety and efficacy, which will benefit consumers and the health care system. It has been suggested that low-cost pharmacokinetic (PK) studies, which monitor concentrations in the blood or urine, could be used to demonstrate equivalence. However, a better understanding of regional and local drug deposition patterns in the lung is required. The objective of this study is to advance the development of an existing CFD model of orally inhaled drug products that can account for inhaler characteristics (spray or air-jet momentum), drug physicochemical properties (aerodynamic size distribution, evaporation and condensation, dissolution) and physiological parameters (breathing pattern, geometry, disease state) on local and regional drug deposition throughout the airways. In a previous study (sponsored by the US FDA) the proposed CFD model accurately predicted mouth-throat (MT) and upper tracheobronchial (TB) deposition from commercial MDI and DPI inhalers, based on validation with concurrent in vitro experiments, and the model was demonstrated to predict drug deposition throughout the entire TB region. In this newly proposed study, the existing CFD model will be extended to predict deposition throughout the lungs (TB and alveolar regions) with the inclusion of wall motion. Models will be developed that can account for intersubject variability in terms of both geometry and inhalation waveforms. An emphasis of the current project will be on comparing both in vitro experiments and CFD predictions with available in vivo studies in terms of lung drug delivery and drug depositional distribution within the airways. To achieve this overall objective, the following specific aims are proposed.
Specific Aim 1 : Development and mesh generation of representative human airway geometries extending from the mouth-throat to the alveolar region Specific Aim 2: Development of characteristic geometries and inhalation conditions that can provide a range of parameters within which inter-subject variability can be assessed for a population Specific Aim 3: Simulation of transport and deposition of polydisperse DPI aerosols in the entire airways of healthy small, medium, and large subjects with different breathing patterns and assess intersubject variability Specific Aim 4: Simulation of transport and deposition of polydisperse drug particles in the entire airways of asthmatic patients with different breathing parameters The CFD model developed in this study will play a valuable role in the areas of inhaler design, selecting appropriate inhalation devices and inhalation flow conditions for optimal lung delivery, and determining bioequivalence between devices. Based on the previous first year of model development, interesting differences in the TB and alveolar delivery between standard MDI and DPI inhalers used with correct and incorrect inhalation profiles were demonstrated. Both the developed CFD model and in vitro tests will be extensively compared with in vivo data and will give researchers two methods for rapidly predicting drug distribution within the airways across a population. This new approach for determining drug deposition in the lungs coupled with low-cost PK data can ultimately be used to establish bioequivalence between generic and innovator products without the need for costly and difficult to interpret pharmacodynamic studies. In addition, the methods proposed are independent of therapeutic class and therefore would be applicable as a universal method for all orally inhaled drug products.

Public Health Relevance

For generic drugs to be approved by the FDA as safe and effective, bioequivalence must be demonstrated with the innovator product. Establishing bioequivalence is currently difficult and expensive for inhaled medications, due to their local action within the lungs. This study develops a new computational fluid dynamics (CFD) model of pharmaceutical aerosol transport and deposition throughout the airways that can account for intersubject variability. The model is validated with concurrent laboratory experiments and existing clinical data on drug deposition in humans. It is proposed that the developed CFD model together with in vitro experimental tests can be used to replace expensive and difficult to interpret human subjects pharmacodynamic studies in establishing bioequivalence for inhaled medications.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01FD004570-02
Application #
8922803
Study Section
Special Emphasis Panel (ZFD1)
Project Start
2012-09-15
Project End
2015-09-14
Budget Start
2014-09-15
Budget End
2015-09-14
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Walenga, Ross L; Longest, P Worth (2016) Current Inhalers Deliver Very Small Doses to the Lower Tracheobronchial Airways: Assessment of Healthy and Constricted Lungs. J Pharm Sci 105:147-59
Rygg, Alex; Hindle, Michael; Longest, P Worth (2016) Linking Suspension Nasal Spray Drug Deposition Patterns to√ā¬†Pharmacokinetic Profiles: A Proof-of-Concept Study Using Computational Fluid Dynamics. J Pharm Sci 105:1995-2004
Longest, P Worth; Tian, Geng; Khajeh-Hosseini-Dalasm, Navvab et al. (2016) Validating Whole-Airway CFD Predictions of DPI Aerosol Deposition at Multiple Flow Rates. J Aerosol Med Pulm Drug Deliv 29:461-481
Delvadia, Renishkumar R; Wei, Xiangyin; Longest, P Worth et al. (2016) In Vitro Tests for Aerosol Deposition. IV: Simulating Variations in Human Breath Profiles for Realistic DPI Testing. J Aerosol Med Pulm Drug Deliv 29:196-206
Tian, Geng; Hindle, Michael; Lee, Sau et al. (2015) Validating CFD Predictions of Pharmaceutical Aerosol Deposition with In Vivo Data. Pharm Res 32:3170-87
Walenga, Ross L; Tian, Geng; Longest, P Worth (2013) Development of characteristic upper tracheobronchial airway models for testing pharmaceutical aerosol delivery. J Biomech Eng 135:91010