Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure

Kivikko, Matti; Antila, Saila; Eha, Jaan; Lehtonen, Lasse; Pentikäinen, Pertti J.

doi:10.5414/cpp40465

Cited by 171 publications

(150 citation statements)

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“…26 Although levosimendan has a half-life of approximately 1 hour, its active metabolite OR-1896 has a half-life of 80 hours. Therefore, a single 24-hour infusion should provide hemodynamic effects over the course of a week, 27 which is long enough to support the majority of patients with septic shock until hemodynamic recovery.…”

Section: Discussionmentioning

confidence: 99%

Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis

et al. 2016

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BACKGROUNDLevosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis. METHODSWe conducted a double-blind, randomized clinical trial to investigate whether levosimendan reduces the severity of organ dysfunction in adults with sepsis. Patients were randomly assigned to receive a blinded infusion of levosimendan (at a dose of 0.05 to 0.2 μg per kilogram of body weight per minute) for 24 hours or placebo in addition to standard care. The primary outcome was the mean daily Sequential Organ Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; maximum score, 20). Secondary outcomes included 28-day mortality, time to weaning from mechanical ventilation, and adverse events. RESULTSThe trial recruited 516 patients; 259 were assigned to receive levosimendan and 257 to receive placebo. There was no significant difference in the mean (±SD) SOFA score between the levosimendan group and the placebo group (6.68±3.96 vs. 6.06±3.89; mean difference, 0.61; 95% confidence interval [CI], −0.07 to 1.29; P = 0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference, 3.6 percentage points; 95% CI, −4.5 to 11.7; P = 0.43). Among patients requiring ventilation at baseline, those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days (hazard ratio, 0.77; 95% CI, 0.60 to 0.97; P = 0.03). More patients in the levosimendan group than in the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolute difference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P = 0.04). CONCLUSIONSThe addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction or lower mortality. Levosimendan was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia. (Funded by the NIHR Efficacy and Mechanism Evaluation Programme and others; LeoPARDS Current Controlled Trials number, ISRCTN12776039.)A BS TR AC T

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Section: Discussionmentioning

confidence: 99%

Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis

et al. 2016

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“…Obach metabolite and cardiovascular effect is observed (Kivikko et al, 2002). Upon cessation of the infusion, levosimendan concentrations drop rapidly.…”

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confidence: 97%

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Obach

2013

Pharmacol Rev

138

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“…Therefore, this drug has a special pharmacokinetic interest: it is one of the few drugs used in cardiovascular medicine, which prolonged action is not due to the drug itself but is mainly due to its active metabolite OR-1896 (approximately 80 hours half life). This metabolite reaches a peak plasma concentration about 2 days after the termination of the infusion and exhibits hemodynamic effects similar to those of levosimendan (16). Because of the long half-life of the active metabolite, these effects last for up to 7 to 9 days after discontinuation of a 24-hour infusion of levosimendan (17).…”

Section: Mechanism Of Effectsmentioning

confidence: 99%