Safety of Lung Delivered Tissue Plasminogen Activator

DESCRIPTION (provided by applicant): The acute respiratory distress syndrome (ARDS) represents a significant health hazard that is associated with high morbidity and mortality rates. Unfortunately, little progress has been made in advancing the treatment of ARDS. Phase I STTR funding supported the successful determination of a feasible formulation of tissue plasminogen activator (tPA) for pulmonary delivery. The successful outcome of phase I established the rationale for studies in animals to determine the safety of lung delivered; this is the primary objective of our phase II application. Thus, this application represents the advancement of work for pharmacological innovation in the treatment of ARDS and extends phase I studies to in vivo animal models to test the hypothesis that pulmonary delivery of tPA will be safe and well tolerated. To this end, the specific aims of this proposal are to: 1) Formulate pulmonary tPA for lung delivery. Mouse and human tPA will be formulated for pre-clinical toxicology and pharmacokinetic (PK)/pharmacodynamic (PD) studies; 2) Assess the tolerability of the pulmonary formulated tPA by assessing both acute (dose escalating) and chronic (repeated dose) toxicity as determined by utilization of a mouse model which will be subjected to pulmonary instillation and intravenous (IV) administration of tPA formulated for lung delivery. These experiments are designed to measure indicators of toxicity such as pulmonary injury, disruption in coagulation homeostasis and hemorrhage; and 3) Determine the PK and PD disposition of pulmonary delivered tPA. This aim will be accomplished by measuring lung and systemic therapeutic protein concentrations following pulmonary and IV administration of the pulmonary formulation in a rat model. These experiments are designed to assess disruption in coagulation homeostasis (PD end point) in the context of systemic tPA concentrations that are achieved following high doses of tPA (toxicokinetics). The anticipated outcomes associated with the successful completion of the work proposed in this application are: 1) establishment of the safety profile of a pulmonary formulation; 2) the development of a risk probability model for the clinical situation; and 3) preparation of an IND application that is required for eligibility for an FDA Orphan Products Grant Application. The proposed Phase II project will complement and extend our Phase I work and will facilitate the development of a promising new, greatly needed therapeutic for the treatment of ARDS.