Subcutaneous Drug Development for Portal Hypertension Ascites

门静脉高压腹水的皮下药物开发

• 批准号: 10469005
• 负责人: Gerardo M. Castillo
• 金额: $ 98.23万
• 依托单位: PHARMAIN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469005
• 关键词: Acute; Alcoholism; American; Animals; Ascites; Binding; Blood; Bolus Infusion; Cessation of life; Chronic; Cirrhosis; Clinical Trials; Confidential Information; Creation of peritoneovascular shunt; Data; Diuretics; Dose; Equilibrium; Europe; Excipients; Fluid overload; Formulation; Functional disorder; Funding; Furosemide; Greater sac of peritoneum; Half-Life; Health Care Costs; Hemorrhage; Hepatic Encephalopathy; Hepatorenal Syndrome; Hospital Costs; Human; Infusion procedures; Injections; Intravenous; Intravenous Bolus; Lead; Liquid substance; Liver Cirrhosis; Liver diseases; Lysine; Medical; Modeling; Modification; Necrosis; No-Observed-Adverse-Effect Level; Operative Surgical Procedures; Orphan Drugs; Outpatients; Paracentesis; Patients; Peritoneal Fluid; Pharmaceutical Preparations; Pharmacology; Phase; Portal Hypertension; Portal vein structure; Practice Guidelines; Prevalence; Procedures; Prodrugs; Quality of life; Rattus; Recommendation; Refractory; Safety; Secure; Small Business Innovation Research Grant; Sodium Chloride; Sodium-Restricted Diet; Spironolactone; Survival Rate; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; Transjugular intrahepatic portosystemic shunt procedure; Transplant Recipients; Urine; Varicosity; Vasopressins; Viral hepatitis; acute care; analytical method; base; cost effective; dietary restriction; drug development; effective therapy; efficacy testing; hemodynamics; infection risk; lead candidate; liquid formulation; liver transplantation; meetings; method development; mortality; nonalcoholic steatohepatitis; pharmacokinetics and pharmacodynamics; phase 1 study; preference; pressure; receptor; side effect; subcutaneous; success

ABSTRACT: 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 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 transplant 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 an inactive pro-drug of Lysine-vasopressin (LVP) that releases active LVP slowly to minimize LVP spike that can cause ischemic side effect. LVP reduces portal vein pressure, restores hemodynamic balance, and is an effective treatment for portal hypertension ascites. Because of slow LVP release, terlipressin is well tolerated and has a far better safety profile than human native 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 varices 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 (26 min) that necessitates administration by IV bolus injection every 4-6h. We developed a new terlipressin derivative (dTer) that has much slower LVP release and found to be effective rat model of cirrhosis induced portal hypertension ascites when administered subcutaneously as once-daily bolus. This product can have a significant market opportunity in the U.S. especially in an outpatient setting (which will reduce overall health care cost by eliminating cost of hospitalization) for the treatment of refractory ascites from cirrhosis- induced portal hypertension ascites. This product (dTer) provides sustained release of active LVP and demonstrated a substantially longer blood presence with lower LVP Cmax (eliminating ischemic side effect) than terlipressin. This proposal is intended to collect IND enabling data package for submission to the FDA to begin clinical trial. We already secured an orphan drug status for the use of dTer in patient with cirrhosis induced ascites. PharmaIN Corp. Confidential Information

摘要：所有类型腹水的患病率，不论病因，为41.7 / 100000