Hemodynamic effects and pharmacokinetics of levosimendan and its metabolites in patients with severe heart failure
Year: 2003
Type: dissertation
Study design: Clinical Trial
Abstract: Levosimendan is a new drug for the treatment of decompensated heart failure. In previous studies, levosimendan has been shown to increase cardiac contractility through myofilament calcium sensitisation and induce peripheral and coronary vasodilation by opening ATP-sensitive potassium channels. The elimination half-life of levosimendan is approximately one hour in man. Preclinical studies have shown that levosimendan has an active metabolite, called OR-1896, with a substantially longer elimination half-life than that of the parent drug. The aims of the present studies were to investigate: (1) the role of levosimendan metabolites on the hemodynamic responses achieved by levosimendan infusion and (2) the pharmacokinetics of levosimendan and its metabolites during and after intravenous levosimendan infusions of different durations in patients with severe heart failure. Levosimendan was administered intravenously for 24 hours to 7 days in a total of 134 patients with NYHA functional class III to IV in three different study settings. Hemodynamics were followed non-invasively in all studies and also invasively in one. Blood samples for pharmacokinetic evaluations were drawn repeatedly in all studies. Safety of the patients was followed by frequent ECG recordings, safety laboratory assessments and adverse event inquiries. Levosimendan infusion increased cardiac output and decreased pulmonary capillary wedge pressure and these effects were sustained for at least 24 hours after stopping the infusion. The effects were accompanied by an increase in heart rate and decrease in blood pressure. After the infusions were stopped, levosimendan rapidly disappeared from blood with an elimination half-life of one hour. In contrast, the plasma concentrations of levosimendan metabolites increased slowly during and even after the infusions and also decreased slowly after the infusions were stopped. The elimination half-life of the active metabolite OR-1896 was 70-80 hours. The hemodynamic effects were prolonged and the changes in hemodynamic variables closely followed the plasma concentrations of OR-1896. Levosimendan was well tolerated in the studies. However, extending the infusion duration beyond 24 hours induced a marked and long-lasting increase in heart rate. In conclusion, the hemodynamic effects of levosimendan were prolonged beyond the infusion period. The prolongation was most likely a consequence of the formation of the active metabolite OR-1896 that has a long elimination half-life. Extending the infusion period beyond 24 hours did not bring any further benefit and was associated with prolonged increase in heart rate.
Source: Työväentutkimus Vuosikirja
Author: Matti Kivikko
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1177836648