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.
Half of patients who develop refractory ascites due to advanced liver cirrhosis will die within a year without a liver transplant. This proposal will develop the desperately needed pharmacological therapies that can stop the progression or extend survival and act as a therapeutic bridge to liver transplantation for these patients. The proposed study involves optimization of an advanced technology formulation of a new terlipressin derivative that can be delivered subcutaneously in an outpatient setting, determine its pharmacokinetics, and test its efficacy in cirrhosis-induced ascites in rat.