Pharmacodynamics and safety of a new calcium sensitizer, levosimendan, and its metabolites during an extended infusion in patients with severe heart failure

Levosimendan is a new calcium sensitizer developed for the short-term intravenous treatment of congestive heart failure. The aims of the present open-label, nonrandomized study were to determine the tolerability, hemodynamic effects, and the basic pharmacokinetics of levosimendon and its metabolites during an extended continuous infusion of levosimendan. Twenty-four patients with New York Heart Association (NYHA) III-IV heart failure in two groups of 12 patients were exposed to either 0.05 mug/kg/min or 0.1 mug/kg/min of levosimendan for 7 days. Heart rate and blood pressure were measured, and blood samples for the determination of plasma concentrations of the parent drug and its metabolites were drawn daily during the infusion and the 10 to 15 days' follow-up. The 7-day infusion was well tolerated and no premature discontinuations occurred. Both systolic and diastolic blood pressure decreased maximally by 6 mmHg in the lower and by 11 mmHg in the higher levosimendan dose groups during the infusion period (p < 0.05 for both groups). The mean heart rate values increased maximally by 18 and 26 beats/min in the lower and higher levosimendan dose groups, respectively (p < 0.001 for both groups). The hemodynamic effects peaked at the end of the infusion period and thereafter slowly declined during the follow-up. After the recommended infusion period of 24 hours, the mean heart rate increase was only 2 and 6 beats/min in the lower and higher levosimendan dose groups, respectively. The elimination half-life of levosimendon was approximately 1 hour and of the metabolites 70 to 80 hours. It can be concluded that levosimendon, even administered considerably longer than the recommended 24 hours, was well tolerated. The 7-day infusion induced a prolonged increase in heart rate and a minor decrease in blood pressure. The long-lasting effects are probably explained by the active metabolite. (C) 2002 the American College of Clinical Pharmacology.