Levosimendan is a
vasodilator used in the treatment of acute
heart failure. In the present study, the effect of hepatic impairment on the pharmacokinetics of
levosimendan and its 2 metabolites,
OR-1855 and
OR-1896 (pharmacologically active), was investigated in 12 healthy subjects and 12 subjects with moderate hepatic impairment due to
alcoholic cirrhosis of the liver but with no
heart failure. In addition, the effect of acetylator status on the pharmacokinetics of
levosimendan,
OR-1855, and
OR-1896 was evaluated. Safety and tolerability of
levosimendan were also assessed.
Levosimendan was given as an
intravenous infusion of 0.1 microg/kg/min for 24 hours.
Levosimendan showed similar C(max), AUC, and elimination half-life (t(1/2)), with a mean (+/-SEM) t(1/2) of 0.9 +/- 0.0 hours in healthy subjects and 0.8 +/- 0.1 hours in hepatically impaired subjects, respectively (not significant). The t(1/2) of
OR-1855 was 61 +/- 5 hours in healthy subjects and 82 +/- 3 hours (P < .01) in subjects with hepatic impairment. The t(1/2) of
OR-1896 was 62 +/- 5 hours and 91 +/- 5 hours (P < .01), respectively. However, the AUCs of
OR-1855 and
OR-1896 were similar in healthy volunteers and hepatically impaired subjects. The effect of acetylator status was seen as higher C(max) and AUC of
OR-1855 in slow acetylators. Correspondingly, higher C(max) and AUC of
OR-1896 were observed in rapid acetylators.
Levosimendan was well tolerated in both study groups. In conclusion, the pharmacokinetics of the parent
drug levosimendan was unaltered in subjects with moderate hepatic impairment, whereas the elimination of the metabolites was prolonged. However, because the maximum duration of
levosimendan infusion is 24 hours, dosing adjustments of
levosimendan may not be required in subjects with impaired hepatic function.