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.

Levosimendan: The current situation and new prospects

“…19 Also, hepatic dysfunction does not warrant a dose adjustment even if the elimination half-life of metabolites is prolonged. 20 Importantly, while some inotropes exhibit tolerance after an infusion of several hours, this was not shown for levosimendan. Lastly, withdrawal is not followed by a rebound effect.…”

Repetitive use of levosimendan in advanced heart failure: need for stronger evidence in a field in dire need of a useful therapy

“…Levosimendan has one active metabolite, coded OR-1896. Both the parent drug and OR-1896 have similar effects, but levosimendan has a half-life of about 1 h, whereas OR-1896 reaches its peak plasma concentration 2-3 days after levosimendan infusion, thus prolonging therapeutic effects beyond the infusion period [19][20][21][22]. The drug was formulated for a 24-hour infusion, after which its pharmacodynamic effects (i.e., increase in cardiac output and reduction of pulmonary capillary wedge pressure) persist for at least one week [23].…”

Utilisation du levosimendan chez l’enfant

“…L'OR-1896 voit sa concentration maximale atteinte 2 jours après le début de la perfusion et est complètement éliminé en 2 semaines, ce qui lui confère un effet prolongé d'au moins 7 jours [9]. Chez des patients ayant une insuffisance hépatique modérée ou une insuffisance rénale sévère, seule l'élimination de l'OR-1896 est prolongée, ce qui n'a pas de conséquence clinique et ne justifie pas d'adaptation de la posologie [10]. Enfin, à la différence d'autres inotropes, il n'y a pas d'effet rebond constaté à la fin de la perfusion.…”