Project Summary / Abstract The rate of FDA approval for respiratory drugs is only 3%, much lower than drugs developed for other key therapeutic areas. The lower success rate for respiratory drugs can be attributed to the lack of innovation for developing inhaled therapeutics, especially tools needed for early drug development phases. The early assessment of a drug’s metabolism, pharmacokinetics, and toxicology (DMPK/tox) are extremely critical. Preclinical animal studies reduce the time and costs expended with the development of new drugs, thus increasing the overall success of bringing new therapies to market. However, for animal models of lung diseases, current methods for airway dosing have major limitations that greatly affect the data quality, reliability and feasibility of DMPK/tox studies. To address these limitations, our proposed project will develop a new tool for use during the preclinical stages of drug development of inhaled therapeutics. We will design and assemble a working prototype of a miniaturized intratracheal device that will produce aerosolized drug particles < 1 µm in size, which is the optimum particle size to allow even drug distribution to the distal lungs. We will then optimize the surgical procedure for implantation of the intratracheal device in the trachea of the rat model, quantify particle deposition in the lung in single and multiple dose studies, and evaluate biocompatibility of the device. Implantable catheters are commonly used for DMPK/tox testing of oral and intravenous drugs, but a technology for an implantable system for inhaled dosing is not yet available. Upon completion of Phase I, we will have a working prototype and surgical implantation methods for an intratracheal device that demonstrates efficient particle distribution in the lungs when administered via airway using single or multiple dosing strategies. This will provide the foundation for Phase II studies, in which we will evaluate costs, conduct comparative DMPK/tox studies with existing inhalation dosing methods, and demonstrate utility in disease models in order to define specific viable market sectors. The integration of a new tool for preclinical development of respiratory drugs will greatly improve the early stage drug development process for respiratory drugs and help advance therapeutics towards FDA approval.

Project Narrative Respiratory disease is a global pandemic, affecting over 1 billion people worldwide. With the rising prevalence of pulmonary disorders, such as asthma and chronic obstructive pulmonary disease, there is an increasing need for new medications. However, the rate of market approval for respiratory drugs is only 3% compared to other diseases, such as cancer and cardiovascular disease. The lower success rate for respiratory drugs can be attributed to the lack of innovation for developing inhaled therapeutics, especially tools needed for the early drug development phases. Currently, in vivo inhalation dosing studies remain difficult, time consuming, expensive, and inaccurate, resulting in poor quality data. To address these challenges, our proposed project will develop a new tool for use during the preclinical, early stages of development of inhaled therapeutics. The early in vivo assessment of a drug’s metabolism, pharmacokinetics, and toxicology (DMPK/tox) are extremely critical. These studies reduce the time and costs expended with the development of new drugs, thus increasing the overall success of bringing new drugs to market. Surgical implantation of catheters in rodents for dosing and sampling are widely used methods for DMPK/tox studies, which range from small scale (early stage development in academic research setting) to large scale (pharmaceutical industry and CRO setting), accommodating single or multiple dosing strategies. However, these methods are limited to dosing and sampling in veins, arteries and GI tract only, which have helped to advance the development of oral and intravenous drugs. The development of an intratracheal device for animal models would fill in this technological gap, enabling the utility of improved inhaled dosing strategies. We anticipate that an implantable intratracheal device would increase the accuracy of respiratory drug studies by improving drug distribution to the distal lung and reduction of stress in freely moving animals. In addition, the intratracheal device will provide cost savings by reducing the loss of drug, reduce excessive use of animals, and importantly, provide reliable data for go/no-go decisions early in preclinical drug development.