Pharmacokinetics of Intravenous Levosimendan and Its Metabolites in Subjects With Hepatic Impairment

Abstract

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.