Effect of severe renal failure and haemodialysis on the pharmacokinetics of levosimendan and its metabolites.
OBJECTIVE
Levosimendan is a calcium sensitiser developed for the treatment of congestive heart failure. It increases myocardial contractility, reduces the filling pressure and dilates both the peripheral and coronary vessels. The circulating metabolites of levosimendan, OR-1855 and OR-1896, are formed and eliminated slowly after intravenous administration of levosimendan. The aim of this study was to investigate the effect of impaired renal function and haemodialysis on the pharmacokinetics of levosimendan, OR-1855 and OR-1896.


METHODS
This study was an open-label, nonrandomised, phase I pharmacokinetic study. Levosimendan was administered as a single-dose infusion of 0.1 microg/kg/minute for 24 hours. The follow-up period lasted 3 weeks.


METHODS
Twenty-fivepatients were included:12 patients with severe chronic renal failure (CRF) with creatinine clearance of < 30 mL/minute/1.73 m(2) and 13 patients with end-stage renal disease (ESRD) undergoing haemodialysis. A group of 12 healthy subjects served as controls.


RESULTS
Levosimendan, the parent drug, was eliminated rapidly from the plasma after discontinuation of its infusion, with an elimination half-life (t(1/2)) [mean +/- standard error of mean] of 1.5 +/- 0.09 hours in ESRD patients undergoing haemodialysis, 1.0 +/- 0.2 hours in patients with severe CRF and 0.91 +/- 0.03 hours in healthy subjects. The t(1/2) of levosimendan was significantly longer (p < 0.001) in ESRD patients undergoing haemodialysis than in healthy subjects. The t(1/2) of OR-1855 and OR-1896 were 94.0 +/- 20.4 hours and 96.5 +/- 19.5 hours, respectively, in ESRD patients undergoing haemodialysis compared with 60.8 +/- 5.2 and 61.6 +/- 5.2 hours, respectively, in healthy subjects (p = not significant). The t(1/2) of OR-1855 was significantly longer (85.0 +/- 13.6 hours) in patients with severe CRF than in healthy subjects (60.8 +/- 5.2 hours, p < 0.05). The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (C(max)) of the metabolites were approximately 2-fold in patients with ESRD undergoing haemodialysis and patients with severe CRF compared with healthy subjects. The mean unbound fraction (f(u)) of levosimendan in plasma was approximately 2% in each study group, whereas the f(u) of the metabolites was considerably higher (63-70%). In contrast to levosimendan, the metabolites were dialysable, with dialysis clearance of approximately 100 mL/minute. The haemodynamic responses and adverse event profiles were similar in the study groups, with headache, palpitations and dizziness being the most frequently recorded adverse events.


CONCLUSIONS
The t(1/2) of the levosimendan metabolites was prolonged 1.5-fold and their AUC and C(max) were 2-fold in patients with severe CRF and ESRD patients undergoing haemodialysis as compared with healthy subjects. These results suggest that the dose should be reduced when levosimendan is used for the treatment of congestive heart failure in patients with severe renal insufficiency.
Puttonen
Jaakko
J
Clinical R&D, Orion Pharma, Kuopio, Finland. jaakko.puttonen@orionpharma.com
Kantele
Sampo
S
Kivikko
Matti
M
Häkkinen
Sari
S
Harjola
Veli-Pekka
VP
Koskinen
Petri
P
Pentikäinen
Pertti J
PJ
D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000465:Algorithms; D019540:Area Under Curve; D001711:Biotransformation; D001794:Blood Pressure / Q000502:physiology; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D006207:Half-Life; D006339:Heart Rate / Q000502:physiology; D006835:Hydrazones / Q000009:adverse effects / Q000493:pharmacokinetics; D007676:Kidney Failure, Chronic / Q000378:metabolism; D007677:Kidney Function Tests; D011485:Protein Binding; D011724:Pyridazines / Q000009:adverse effects / Q000493:pharmacokinetics; D006435:Renal Dialysis / Q000009:adverse effects; D000077464:Simendan
D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan