In Vivo–In VitroCorrelations: Predicting Pulmonary Drug Deposition from Pharmaceutical Aerosols

Abstract

In order to answer the question "what research remains to be done?" we review the current state of the art in pharmaceutical aerosol deposition modeling and explore possible in vivo- in vitro correlations (IVIVC) linking drug deposition in the human lung to predictions made using in vitro physical airway models and in silico computer models. The use of physical replicas of portions of the respiratory tract is considered, alongside the advantages and disadvantages of the different imaging methods used to obtain their dimensions. The use of airway replicas to determine drug deposition in vitro is discussed and compared with the predictions from different empirical curve fits to long-standing in vivo deposition data for monodisperse aerosols. The use of improved computational models and three-dimensional computational fluid dynamics (CFD) to predict aerosol deposition within the respiratory tract is examined. CFD's ability to predict both drug deposition from pharmaceutical aerosol sprays and powder behavior in dry powder inhalers is examined; both were highlighted as important areas for future research. Although the authors note the abilities of current in vitro and in silico methods to predict in vivo data, a number of limitations remain. These include our present inability to either image or replicate all but the most proximal airways in sufficient spatial and temporal detail to allow full capture of the fluid and aerosol mechanics in these regions. In addition, the highly complex microscale behavior of aerosols within inhalers and the respiratory tract places extreme computational demands on in silico methods. When the complexity of variations in respiratory tract geometry is associated with additional factors such as breathing pattern, age, disease state, postural position, and patient-device interaction are all considered, it is clear that further research is required before the prediction of all aspects of inhaled pharmaceutical aerosol deposition is possible.

Validating Whole-Airway CFD Predictions of DPI Aerosol Deposition at Multiple Flow Rates

“…(2,9,10) However, predicting regional and local aerosol deposition throughout the airways may require more advanced modeling techniques. (11,12) It is expected that regional and local deposition patterns of drugs in the lungs will influence efficacy and treatment success. (13,14) Furthermore, efficacy also depends on drug dissolution, absorption, and clearance.…”

In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches

“…The Orlando meeting builds upon, among other things, the published outputs from the "Thousand Years of Pharmaceutical Aerosols" meeting in Iceland 5 years ago which considered the question "what remains to be done in the field of pharmaceutical aerosol science" (1). In vitro testing of OIP was reviewed in outputs from the meeting in Iceland (2,3). In this article, we consider subsequent developments and the extent to which research priorities are being addressed.…”

Effect of Device Design on the In Vitro Performance and Comparability for Capsule-Based Dry Powder Inhalers

“…The complex relationship between the physicochemical properties of the powder dose and the design of the DPI device will ultimately control the fluidization, deaggregation, and aerodynamic particle size of the drug particles (6). This in turn will influence the regional deposition of drug particles in the lung and thus the safety and efficacy of a DPI (7). Hence, in order to produce a test DPI that closely matches the in vitro performance of the reference DPI, it is important to investigate the fluidization and deaggregation behavior of the The opinions expressed in this paper by the authors do not necessarily reflect the views or policies of the Food and Drug Administration (FDA).…”