Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure.
OBJECTIVE
Levosimendan is a new calcium sensitizer with additional vasodilatory properties developed for the short-term intravenous treatment of congestive heart failure. The aims of the present study were to determine the pharmacokinetics and hemodynamic effects of levosimendan and its metabolites during and after a 24-hour levosimendan infusion.


METHODS
The study was an open-label, non-randomized, phase II study in 2 centers. Twelve patients with NYHA III-IV heart failure received 0.2 microg/kg/min continuous infusion of levosimendan for 24 hours. Blood samples for the determination of plasma concentrations of the parent drug and the metabolites were drawn repeatedly during the infusion and the 2-week follow-up period. Heart rate from Holter recordings and blood pressure were measured.


RESULTS
The elimination half-life of levosimendan was 1.3 hours and that of the metabolites 75-78 hours. The mean maximum increase in heart rate of 10 bpm (p < 0.005) and the mean maximum decreases in systolic and diastolic blood pressure of 12 mmHg and 8 mmHg (p < 0.05 for both), respectively, were observed during the first day after stopping levosimendan infusion. The hemodynamic effects slowly declined during the follow-up, and after 1 week no statistically significant differences compared with baseline were observed. No increase in ventricular arrhythmias was seen.


CONCLUSIONS
A 24-hour infusion of levosimendan induces hemodynamic effects lasting several days after stopping the infusion. The prolongation of the effects beyond the infusion period is most likely due to an active metabolite with a long half-life.
Kivikko
M
M
Orion Pharma, Cardiovascular Projects, Espoo, Finland. matti.kivikko@orionpharma.com
Antila
S
S
Eha
J
J
Lehtonen
L
L
Pentikäinen
P J
PJ
D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011724:Pyridazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000077464:Simendan; D013997:Time Factors
D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan