Subcutaneous Drug Development for Portal Hypertension Ascites

描述(申请人提供)：所有类型腹水的患病率，无论原因如何，每10万人中有41.7人，其中80%是由肝硬变引起的。腹水的治疗采用限盐饮食和利尿剂的药物治疗。然而，在5%到10%的腹水患者中，腹水对药物治疗变得难以治疗。由于晚期肝硬变而出现顽固性腹水的患者中，有一半将在没有肝移植计划的情况下在一年内死亡，因此建议加快转诊进行肝移植。等待期间的临时治疗包括大容量穿刺术、经颈静脉肝内门体分流术(TIPS)和腹膜静脉分流术。这些手术的并发症会进一步增加死亡率，包括穿刺术引起的循环功能障碍(PICD)和TIPS的慢性肝性脑病。因此，迫切需要能够阻止病情发展或延长存活期并充当肝移植治疗桥梁的药物疗法。特利加压素是一种合成肽类药物，可降低门静脉压力，恢复血流动力学平衡，是治疗门脉高压腹水的有效药物。这种前药在血液中缓慢转化为血管活性物质[8-lys]加压素；它具有良好的耐受性，并且比人的Nativ加压素([8-Arg]加压素)具有更好的安全性。静脉注射特利加压素在欧洲已经有20年的历史了，它是治疗各种出血和肝肾综合征(HRS)的最具成本效益和最经济的药物之一，并能提高存活率，这是有充分证据的。尽管特利加压素具有良好的安全性，但目前仅限于急性护理环境中使用，因为其半衰期短(26分钟)，需要每隔4-6小时静脉推注一次。我们相信，一种新的特利加压素衍生物的配方可以每天给药一次，最好是皮下注射，并将在美国的门诊环境中拥有巨大的市场机会(这将降低整体医疗成本)，用于治疗肝硬变引起的门脉高压症所致的顽固性腹水。我们基于PI发明的专利给药技术开发了一种新的长效特利加压素(LAT)，该技术可以使修饰的特利加压素持续释放。LATT的半衰期明显长于未经修饰的特利加压素多肽(分别为3.3小时和0.8小时)，并被观察到可在20小时以上保持可测量的血药浓度，而快速清除特利加压素的半衰期为5小时。本研究将优化处方，测定各种代谢物的药代动力学，以确定所需的最佳剂量，并测试该制剂治疗大鼠肝硬化性腹水的疗效。

DESCRIPTION (provided by applicant): The prevalence of all types of ascites, irrespective of the cause, is 41.7 in 100,000 with 80% of these due to cirrhosis. Ascites is treated with a salt restricted diet and pharmacologic therapy using diuretics. However, in 5% to 10% of patients with ascites, the ascites becomes refractory to medical therapy. Half of patients who develop refractory ascites due to advanced liver cirrhosis will die within a year without a liver transplan and therefore expedited referral for liver transplantation is recommended. Temporary treatment while waiting includes large volume paracentesis, transjugular intrahepatic portasystemic shunt (TIPS), and peritoneovenous shunt surgical procedures. Complications from these procedures that can further increase mortality include paracentesis-induced circulatory dysfunction (PICD) and chronic hepatic encephalopathy from TIPS. Pharmacological therapies that can stop the progression or extend survival and act as a therapeutic bridge to liver transplantation are thus desperately needed. Terlipressin, tri-glycyl [8-lys] vasopressin, is a synthetic peptide drug that reduces portal vein pressure, restores hemodynamic balance, and is an effective treatment for portal hypertension ascites. This prodrug is slowly converted to the vasoactive agent [8-lys] vasopressin in the blood; it is well tolerated and has a far better safety profile than human nativ vasopressin ([8-Arg] vasopressin). Intravenous terlipressin has been available in Europe for the past twenty years and it is one of the most cost-effective and economical drugs for treating bleeding varies and hepatorenal syndrome (HRS) with improvement in survival rates that is well documented. Despite its good safety profile, the use of terlipressin is currently limited to the acute care setting because the short half-life (26min) necessitates administration by IV bolus injection every 4-6h. We believe that a formulation of a new terlipressin derivative that can be administered once-daily, ideally subcutaneously, and would have a significant market opportunity in the U.S. in the outpatient setting (which will reduce overall health care cost) for the treatment of refractory ascites from cirrhosis-induced portal hypertension. We developed a new long acting terlipressin (LAT) based on a proprietary drug delivery technology invented by the PI that gives sustained release of modified terlipressin. LAT demonstrated a substantially longer half-life than unmodified terlipressin peptide (3.3 hours vs. 0.8 hours respectively) and was observed to maintain measurable blood concentrations for more than 20 hours, compared to 5 hours for a rapid clearing of terlipressin. This study will optimize the formulation, determin pharmacokinetics of various metabolites to determine the optimum dose needed, and test the efficacy of the formulation for the treatment of cirrhosis-induced ascites in rat.