Pharmacodynamics and Safety of a New Calcium Sensitizer, Levosimendan, and Its Metabolites during an Extended Infusion in Patients with Severe Heart Failure

Abstract

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 levosimendan 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 microg/kg/min or 0.1 microg/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 levosimendan was approximately 1 hour and of the metabolites 70 to 80 hours. It can be concluded that levosimendan, 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.

Outcome of Prophylactic Use of Levosimendan andMilrinone in Open Heart Surgery With CompromisedVentricular Function–A Comparative Study

“…Experimental reports have also observed increased blood flow with levosimendan to various tissues including the gastric mucosa, renal medulla, small intestine, and liver. [25,26] Levosimendan has an active metabolite which has similar hemodynamic effects [10][11][12] and has a long elimination half life of around 70 to 80 hours. [12] This can be an explanation of its positive hemodynamic effects lasted even after the 24-hour infusion, Levosimendan may constitute a cost effective option as it decreases significantly ICU and hospital stay and consequent risk of complications after open-heart surgery in high risk patients with compromised cardiac function.…”

“…Incidence of hypercalcemia and arrhythmia are also less with it. It has a long acting metabolite with a half-life of 80 h. [10][11][12][13] Levosimendan improves the function of stunned myocardium in patients with acute myocardial infarction undergoing angioplasty. [14] Section: Anaesthesia…”

Levosimendan has a prolonged antispasmodic effect in isolated human radial artery bypass grafts and inhibits thrombin-induced aggregation of human platelets in vitro

“…The receptor independent contraction with high KCl was also larger in RA than IMA, a result that has also been obtained by others [50]. In our study, contractions with heart [39,53]. Levosimendan has both inotropic and vasodilating effects in this concentration [54][55][56][57].…”

“…It has been demonstrated recently that a single loading dose of the inodilator would normalize the hemodynamic conditions including total peripheral resistance days after bypass graft surgery [35]. Active metabolite(s) with long half-life has been suggested to be responsible -at least in part -for this longlasting effect of levosimendan in vivo [53]. However, our present observation in vitro provides evidence that the drug by itself and not its metabolite(s) is able to decrease the contractions of the RA graft.…”

“…In PRP, the 10% IC of levosimendan (IC 10 =0.07 µmol/L) is at the lower level of the in vivo range with peak concentrations between 0.12-0.2 µmol/L [43,53].…”