Safety, Tolerability, Pharmacokinetics, and Efficacy of Terlipressin Delivered by Continuous Intravenous Infusion in Patients with Cirrhosis and Refractory Ascites

Abstract

Background. Terlipressin is a long acting synthetic analogue of vasopressin, which is used to manage variceal bleeding and hepatorenal syndrome. Terlipressin is being developed to treat refractory ascites in cirrhotic patients who are no longer responsive to diuretic drugs and require repeated paracentesis. This study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of a continuous intravenous (IV) infusion of terlipressin as an outpatient treatment for refractory ascites in patients with advanced liver cirrhosis. Methods. This was an open-label Phase 2a trial. Patients received a continuous IV infusion of terlipressin 2 mg/day escalating to 4 mg/d during an initial 7-day inpatient period, followed by 21 days as outpatients. The PK, safety/tolerability, and effects on the need for and volume of paracentesis were evaluated. Results. Four of 6 patients experienced ≥50% increase in the interval between large volume paracenteses (LVP) with terlipressin. The volume of ascites removed by LVP in the 28-day treatment period was reduced in all patients by ≥30% compared with pretreatment. Terlipressin was rapidly eliminated with a mean half-life of 42.3 minutes, mean clearance of 5.6 mL/min/kg, and volume of distribution of 0.33 L/kg. Average steady state plasma concentrations ranged from 1.69 to 5.55 ng/mL and increased proportionally with increasing dose. Three (50.0%) patients reported treatment-related adverse events, but none were serious. Conclusion. Continuous terlipressin IV infusion improved control of refractory ascites with an acceptable safety and predictable PK profile. Further evaluation of terlipressin is warranted in a randomized controlled trial for treating refractory ascites and related complications of cirrhosis.