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. MATERIALS: 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.

Metabolism of OR-1896, a metabolite of levosimendan, in rats and humans.

OR-1896 is a pharmacologically active, long-lived metabolite of levosimendan. In the current study, the metabolism of (14)C-labelled OR-1896 was investigated in six healthy men after intravenous infusion over 10 min and in male rats after an intravenous bolus dose. In human plasma, the only (14)C-compounds detected were (14)C-OR-1896 and its deacetylated form, (14)C-OR-1855, in varying proportions in different subjects. In rat plasma >93% of radioactivity was associated with OR-1896. Radioactivity was mainly excreted to urine in both rats (about 69% of the dose) and humans (about 87% of the dose). OR-1896 was a major urinary compound in both humans and rats. Another major human metabolite was hypothesized as N-conjugated OR-1855. Other human and rat urinary biotransformation products were characterized as N-hydroxylated OR-1896 and N-hydroxylated OR-1855, as well as glucuronide or sulphate conjugates of N-hydroxyl OR-1896. The main difference between rat and human metabolism was a lower amount of OR-1855-related metabolites in the rats. In human faecal homogenates, only OR-1896 and OR-1855 were detected, whereas rat faecal metabolite profile was similar to that in urine.