Safety of Lung Delivered Tissue Plasminogen Activator

描述（由申请人提供）：急性呼吸窘迫综合征（ARDS）是一种与高发病率和高死亡率相关的重大健康危害。不幸的是，在推进ARDS治疗方面进展甚微。第一阶段STTR资助成功确定了用于肺输送的组织型纤溶酶原激活剂（tPA）的可行配方。第一阶段的成功结果为动物试验确定肺给药的安全性奠定了基础；这是我们II期应用的主要目标。因此，这一应用代表了治疗ARDS的药理学创新工作的进展，并将I期研究扩展到体内动物模型，以验证肺给药tPA安全且耐受性良好的假设。为此，本提案的具体目的是：1)制定肺输送tPA。小鼠和人tPA将用于临床前毒理学和药代动力学(PK)/药效学（PD）研究；2)通过评估急性（剂量递增）和慢性（重复剂量）毒性来评估肺配方tPA的耐受性，这是通过使用小鼠模型来确定的，小鼠模型将接受肺滴注和静脉（IV）给药。这些实验旨在测量毒性指标，如肺损伤、凝血稳态破坏和出血；3)确定肺传递tPA的PK和PD配置。这一目标将通过在大鼠模型中肺和静脉给药后测量肺和全身治疗蛋白浓度来实现。这些实验旨在评估在高剂量tPA（毒性动力学）后达到全身tPA浓度的情况下凝血稳态（PD终点）的破坏。与成功完成本申请中提出的工作相关的预期结果是：1)建立肺制剂的安全性概况；2)建立临床情况的风险概率模型；3)准备IND申请，该申请是获得FDA孤儿产品许可申请资格所必需的。拟议的第二期项目将补充和扩展我们的第一期工作，并将促进开发一种有前途的新的，急需的治疗ARDS的药物。

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.