Research Project
9312294
? DESCRIPTION (provided by applicant): Pulmonary drug delivery has emerged as a noninvasive alternative route for the treatment of lung diseases (asthma, COPD, CF and lung cancer). In order to obtain the desired level of effectiveness and safety of the inhaled drugs, an appropriate deposition on the targeted region and subsequent absorption in the targeted region is vital. Multiscale multidisciplinary computational tools, linking Computational Fluid Dynamics (CFD), particle/species transport and PBPK-PD models, were developed during the Phase I effort for obtaining mechano-biological insights and quantifying the efficacy of the delivery processes. Preliminary results demonstrated the validity and capabilities of this multiscale multidisciplinary computational concept. In Phase II, we will (i) extend the existing particle transport models for handling varied drug sizes, (ii) further develop the deposition formulations for the Reduced Order Models (ROM) for faster than life simulations, (iii) incorporate the airway wall biomechanics model for accurately capturing the dynamics of lumen diameter change, smooth muscle force, particle transport/deposition in healthy and diseased lung states (global or local, levels of progression), (iv) extend and validate the mucosal transport/clearance models on ROM wire meshes to characterize the effects of healthy and diseased states on drug clearance and absorption in the lung tissue, (v) calibrate the models for matching clinical PBPK data for various drugs and administration protocols and (vi) significantly improve the existing GUI for lung geometry alteration (support diseased states) and for the whole-body PBPK. The above aims will hasten the development of pulmonary drugs by carefully identifying key mechanical and biopharmaceutical factors affecting efficacy and safety of inhaled drugs using fast and robust computational simulations. A multistep simulation protocol for modeling drug inhalation delivery, deposition, absorption and PBPK/PD will be established. High fidelity tools will be targeted for pharma expert users and automated fast running reduced order models for pharma end users. The proposed computational toolkit will thus provide a virtual platform to investigate interactions between drug delivery methods, drug/carrier types and the human physiological systems at multiple scales and ultimately optimize the efficacy of pulmonary drug delivery process
