Population pharmacokinetics of levosimendan in patients with congestive heart failure.
OBJECTIVE
The aim of this study was to characterize the population pharmacokinetics of levosimendan in patients with heart failure (NYHA grades III and IV) and its relationship to demographic factors, disease severity and concomitant use of digoxin and beta-blocking agents.


METHODS
Data from two efficacy studies with levosimendan administered by intravenous infusion were combined (190 patients in total). The data were analysed using a nonlinear mixed-effects modelling approach as implemented in the NONMEM program. The model development was done in three sequential steps. First the best structural model was determined (e.g. a one-, two- or three-compartment pharmacokinetic model). This was followed by the identification and incorporation of important covariates into the model. Lastly the stochastic part of the model was refined.


RESULTS
A two-compartment model best described levosimendan pharmacokinetics. Clearance and the central volume of distribution were found to increase linearly with bodyweight. No other covariates, including concomitant use of digoxin and beta-blocking agents, influenced the pharmacokinetics. In the final model, a 76-kg patient was estimated to have a clearance +/- s.e. of 13.3 +/- 0.4 l h-1 and a central volume of distribution of 16.8 +/- 0.79 l. The interindividual variability was estimated to be 39% and 60% for clearance and central volume of distribution, respectively. Weight changed clearance by 1.5% [95% confidence interval (CI) 0.9%, 2.1%] and the central volume of distribution by 0.9% (95% CI 0.5%, 1.3%) per kg.


CONCLUSIONS
The population pharmacokinetics parameters of levosimendan in this patient group were comparable to those obtained by traditional methods in healthy volunteers and patients with mild heart failure. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted for by weight adjusting doses. None of the other covariates, including digoxin and beta-blocking agents, significantly influenced the pharmacokinetics of levosimendan.
Jonsson
E Niclas
EN
Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden. niclas.jonsson@farmbio.uu.se
Antila
Saila
S
McFadyen
Lynn
L
Lehtonen
Lasse
L
Karlsson
Mats O
MO
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004077:Digoxin / Q000627:therapeutic use; D004311:Double-Blind Method; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D006835:Hydrazones / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D011724:Pyridazines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077464:Simendan
D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan; D004077:Digoxin