The hemodynamic and pharmacokinetic interactions between chronic use of oral levosimendan and digoxin in patients with NYHA Classes II-III heart failure.
OBJECTIVE
Levosimendan is a calcium-sensitizing drug for the treatment of heart failure. The aim of this exploratory study was to assess the hemodynamic and pharmacokinetic interactions between digoxin and oral levosimendan as well as the proarrhythmic potential of this combination in patients with chronic heart failure.


METHODS
Male or female patients (n = 24) with chronic heart failure of NYHA Classes II-III.


METHODS
A randomized, placebo-controlled, double-blind, parallel-group trial. After a 1-week digoxin-free washout period, the patients were randomized to receive either digoxin and levosimendan (digoxin + levosimendan), or digoxin and placebo (digoxin) orally for 14 +/- 2 days. The levosimendan dose was 1 mg 3 times daily, and the digoxin dose was 0.125-0.25 mg once daily. Systolic time intervals, electrocardiography (ECG), magneto-cardiography (MCG) and 24-h ambulatory ECG were performed at baseline and at the end of each treatment period. Pharmacokinetic variables of levosimendan and digoxin were calculated in both treatment periods. Steady-state concentrations of the active metabolites OR-1855 and OR-1896 were determined at baseline at Visit 2.


RESULTS
There tended to be a greater shortening of QS2i (suggesting trend to positive inotropy) in the digoxin + levosimendan group (-14ms) compared with the digoxin group (-5ms), although the difference was not statistically significant (p=0.359). However, the change from baseline in QS2i after digoxin + levosimendan was of statistically borderline significance (p=0.05). The change from baseline in the digoxin group was not statistically significant. ECG and MCG repolarization measures and occurrence of nonsustained ventricular tachycardia showed no substantial differences. After 2 weeks of digoxin + levosimendan treatment, mean area under the curve (AUC) of levosimendan increased approximately by 49% (p<0.01). The maximum plasma concentration (Cmax) of levosimendan increased from 17 to 23 ng/ml. The mean concentrations of the metabolites OR-1855 and OR-1896 in plasma were 4.3 and 8.3 ng/ml, respectively.


CONCLUSIONS
The addition of oral levosimendan to digoxin therapy produced only a modest statistically nonsignificant additive inotropic effect. In contrast to the earlier data with intravenous levosimendan, the results indicate a pharmacokinetic interaction between levosimendan and digoxin. Data obtained from repolarization analyses and ambulatory ECG did not indicate any possible proarrhythmic effects of the combination.
Harjola
V-P
VP
Division of Emergency Care, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. veli-pekka.harjola@hus.fi
Oikarinen
L
L
Toivonen
L
L
Jurkko
R
R
Puttonen
J
J
Sarapohja
T
T
Sundberg
S
S
Nieminen
M S
MS
D000081:Acetamides / Q000493:pharmacokinetics; D000284:Administration, Oral; D000368:Aged; D019540:Area Under Curve; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D002908:Chronic Disease; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000493:pharmacokinetics* / Q000494:pharmacology; D053798:Magnetocardiography; D008297:Male; D008875:Middle Aged; D011724:Pyridazines / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077464:Simendan
D000081:Acetamides; D002316:Cardiotonic Agents; D006835:Hydrazones; C414222:N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; D011724:Pyridazines; D000077464:Simendan; D004077:Digoxin