A Diarylheptanoid Scaffold to Treat Taopathies

DESCRIPTION: Pulmonary drug delivery is increasingly used for both treatment of lung diseases (such as asthma and chronic obstructive pulmonary disease) and in delivering drugs to the systemic circulation. To reach the desired effectiveness and safety oforally/nasally inhaled drugs, appropriate deposition of drugs on targeted region is essential. Due to complex pharmaceutical and physiological factors underlying bioavailability of inhaled drug products, computational modeling tools are urgently required to provide mechanistic insights of involved delivery processes and to estimate efficacy of pulmonary drug delivery in an accurate and efficient manner. Therefore, in this project, we propose to develop a novel multi-scale computational tool to simulate deposition, dissolution, absorption, transport, clearance, and actions of inhaled drug products within an integral framework of computational fluid dynamics (CFD) and PBPK-PD models. In Phase I, we will (1.) develop the hybrid CFD model of particle depositionin the entire human airways, (2.) extend the CFD models accounting for various physiological and pathological settings, and (3.) integrate CFD deposition models with pharmacokinetic models to estimate various pharmaceutical and physiological factors on pulmonary drug delivery. The associated computational investigations will greatly facilitate drug development by identifying key biopharmaceutical factors affecting efficacy and safety of inhaled drugs. In Phase II, we will further improve the computational tool model developed in Phase I by focusing on integration with physiology and compound databases, model calibration/validation, development of the software GUI, and demonstration of more pharmaceutical applications. The proposed computational tool will provide a mechanism-based virtual platform to investigate interactions between drug delivery systems and physiological/pathological systems, to provide mechanistic insights into key aspects affecting efficacy and safety of inhaled drug products, and to guideoptimal designs of pulmonary drug delivery systems. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The novel software tool proposed in this project will provide an efficient and accurate computational platform to virtually test, design, anddevelop inhaled drug products by investigating interactions between pulmonary delivery systems and the human physiological systems at multiple scales. Applications of the proposed computational tool will reveal key aspects affecting fate of administered drugs and consequent therapeutic or toxic effects. Hence, the developed computational tool will meet urgent demands from pharmaceutical and biomedical industries by accelerating drug discovery and development processes, by facilitating translational applications from bench to bedside, by increasing success rates of new pulmonary drug products, and by ultimately helping reduce health care burdens on society.