Levosimendan

Chemical formula: C₁₄H₁₂N₆O  Molecular mass: 280.285 g/mol  PubChem compound: 3033825

Mechanism of action

Levosimendan enhances the calcium sensitivity of contractile proteins by binding to cardiac troponin C in a calcium-dependent manner. Levosimendan increases the contraction force but does not impair ventricular relaxation. In addition, levosimendan opens ATP-sensitive potassium channels in vascular smooth muscle, thus inducing vasodilatation of systemic and coronary arterial vessels and systemic venous vessels. Levosimendan has demonstrated selective phosphodiesterase III inhibitor properties in vitro. The relevance of this at therapeutic concentrations is unclear. In patients with heart failure, the positive calcium-dependent inotropic and vasodilatory actions of levosimendan result in an increased contractile force and a reduction in both preload and after load, without adversely affecting diastolic function. Levosimendan activates stunned myocardium in patients after percutaneous transluminal coronary angioplasty (PTCA) or thrombolysis.

Pharmacodynamic properties

Haemodynamic studies in healthy volunteers and in patients with stable and unstable heart failure have shown a dose-dependent effect of levosimendan given intravenously as loading dose (3 μg/kg to 24 μg/kg) and continuous infusion (0.05 to 0.2 μg/kg per minute). Compared with placebo, levosimendan increased cardiac output, stroke volume, ejection fraction and heart rate and reduced systolic blood pressure, diastolic blood pressure, pulmonary capillary wedge pressure, right atrial pressure and peripheral vascular resistance.

Levosimendan infusion increases coronary blood flow in patients recovering from coronary surgery and improves myocardial perfusion in patients with heart failure. These benefits are achieved without a significant increase in myocardial oxygen consumption. Treatment with levosimendan infusion significantly decreases circulating levels of endothelin-1 in patients with congestive heart failure. It does not increase plasma catecholamine levels at recommended infusion rates.

Pharmacokinetic properties

General

The pharmacokinetics of levosimendan are linear in the therapeutic dose range 0.05-0.2 μg /kg/min.

Distribution

The volume of distribution of levosimendan (Vss) is approximately 0.2 L/kg. Levosimendan is 97-98% bound to plasma proteins, primarily to albumin. For OR-1855 and OR-1896, the mean protein binding values were 39% and 42%, respectively in patients.

Metabolism

A major part of the levosimendan dose is metabolised by conjugation to cyclic or N-acetylated cysteinylglycine and cysteine conjugates. Only about 5% of the levosimendan is metabolised in the intestine by reduction to aminophenylpyridazinone (OR-1855), which after reabsorption to the systemic circulation is metabolised in the plasma by N-acetyltransferase to the active metabolite OR-1896. The acetylation level is genetically determined. In rapid acetylators, the concentrations of the metabolite OR-1896 are slightly higher than in slow acetylators. However, this has no implication for the clinical hemodynamic effect at recommended doses.

In systemic circulation the only significant detectable metabolites following levosimendan administration are OR-1855 and OR-1896. These metabolites in vivo reach equilibrium as a result of acetylation and de-acetylation metabolic pathways, which are governed by N-acetyl transferase-2, a polymorphic enzyme. In slow acetylators, the OR-1855 metabolite predominates, while in rapid acetylators the OR-1896 metabolite predominates. The sum of exposures for the two metabolites is similar among slow and rapid acetylators, and there is no difference in the haemodynamic effects between the two groups. The prolonged haemodynamic effects (lasting up to 7-9 days after discontinuation of a 24 hour levosimendan infusion) are attributed to these metabolites.

In vitro studies have shown that levosimendan, OR-1855 and OR-1896 do not inhibit CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 at concentrations achieved by the recommended dosing. In addition levosimendan does not inhibit CYP1A1 and neither OR-1855 nor OR-1896 inhibit CYP2C9. The results of drug interaction studies in humans with warfarin, felodipine and itraconazole confirmed that levosimendan does not inhibit CYP3A or CYP2C9, and metabolism of levosimendan is not affected by CYP3A inhibitors.

Elimination and excretion

Clearance is about 3.0 mL/min/kg and a half-life about 1 hour. 54% of the dose is excreted in urine and 44% in faeces. More than 95% of the dose is excreted within one week. Negligible amounts (<0.05% of the dose) are excreted as unchanged levosimendan in the urine. The circulating metabolites OR-1855 and OR-1896 are formed and eliminated slowly. Peak plasma concentrations for OR-1855 and OR-1896 are reached about 2 days after termination of a levosimendan infusion. The half-lives of the metabolites are about 75-80 hours. Active metabolites of levosimendan, OR-1855 and OR-1896, undergo conjugation or renal filtration, and are excreted predominately in urine. Potential interactions can not be predicted.

Special Populations

Children

Levosimendan should not be administered to children as there is very limited experience using levosimendan in children and adolescents under 18 years of age. Limited data indicate that the pharmacokinetics of levosimendan after a single dose in children (age 3 months to 6 years) are similar to levosimendan in adults. The pharmacokinetics of the active metabolites have not been investigated in children.

Renal impairment

The pharmacokinetics of levosimendan have been studied in subjects with varying degrees of renal impairment who did not have heart failure. Exposure to levosimendan was similar in subjects with mild to moderate renal impairment and in subjects undergoing haemodialysis, while the exposure to levosimendan may be slightly lower in subjects with severe renal impairment.

Compared to healthy subjects, the unbound fraction of levosimendan appeared to be slightly increased, and AUCs of the metabolites (OR-1855 and OR-1896) were up to 170% higher in subjects with severe renal impairment and patients undergoing haemodialysis. The effects of mild and moderate renal impairment on the pharmacokinetics of OR-1855 and OR-1896 are expected to be less than those of severe renal impairment.

Levosimendan is not dialyzable. While OR-1855 and OR-1896 are dialyzable, the dialysis clearances are low (approximately 8-23 mL/min) and the net effect of a 4-hour dialysis session on the overall exposure to these metabolites is small.

Hepatic impairment

No differences in the pharmacokinetics or protein binding of levosimendan were found in subjects with mild or moderate cirrhosis versus healthy subjects. The pharmacokinetics of levosimendan, OR-1855 and OR-1896 are similar between healthy subjects and subjects with moderate hepatic impairment (Child-Pugh Class B), with the exception that elimination half-lives of OR-1855 and OR-1896 are slightly prolonged in subjects with moderate hepatic impairment.

Population Pharmacokinetic Analyses

Population analysis has shown no effects of age, ethnic origin or gender on the pharmacokinetics of levosimendan. However, the same analysis revealed that volume of distribution and total clearance are dependent on weight.

Preclinical safety data

Levosimendan has been evaluated in clinical trials involving over 2800 heart failure patients. The efficacy and safety of levosimendan for the treatment of ADHF were assessed in the following randomised, double-blind, multi-national clinical trials: REVIVE Programme.

REVIVE I

In a double-blind, placebo-controlled pilot study in 100 patients with ADHF who received a 24 hour infusion of levosimendan, a beneficial response as measured by the clinical composite endpoint over placebo plus standard of care was observed in the levosimendan-treated patients.

REVIVE II

A double-blind, placebo-controlled pivotal study in 600 patients who were administered a 10 minute loading dose of 6-12 μg/kg followed by a protocol-specified stepped titration of levosimendan to 0.05-0.2 μg/kg/minute for up to 24 hours that provided a benefit in clinical status in patients with ADHF who remained dyspnoeic after intravenous diuretic therapy.

The REVIVE clinical programme was designed to compare the effectiveness of levosimendan plus standard-of-care to placebo plus standard-of-care in the treatment of ADHF.

Inclusion criteria included patients hospitalised with ADHF, left ventricular ejection fraction less than or equal to 35% within the previous 12 months, and dyspnoea at rest. All baseline therapies were allowed, with the exception of intravenous milrinone. Exclusion criteria included severe obstruction of ventricular outflow tracts, cardiogenic shock, a systolic blood pressure of ≤90 mmHg or a heart rate ≥120 beats per minute (persistent for at least five minutes), or a requirement for mechanical ventilation.

The results of the primary endpoint demonstrated that a greater proportion of patients were categorised as improved with a smaller proportion of patients categorised as worsened (p-value 0.015) as measured by a clinical composite endpoint reflecting sustained benefits to clinical status over three time points: six hours, 24 hours and five days. B-type natriuretic peptide was significantly reduced vs. placebo and standard of care at 24 hours and through five days (p-value=0.001).

The levosimendan group had a slightly higher, although not statistically significant, death rate compared with the control group at 90 days (15% vs. 12%). Post hoc analyses identified systolic blood pressure <100 mmHg or diastolic blood pressure <60 mmHg at baseline as factors increasing the mortality risk.

SURVIVE

A double-blind, double-dummy, parallel group, multicentre study comparing levosimendan vs. dobutamine evaluated 180 day mortality in 1327 patients with ADHF who required additional therapy after an inadequate response to intravenous diuretics or vasodilators. The patient population was generally similar to the patients in the REVIVE II study. However, patients without a previous history of heart failure were included (e.g. acute myocardial infarction), as were patients requiring mechanical ventilation. Approximately 90% of patients entered the trial due to dyspnoea at rest.

The results of SURVIVE did not demonstrate a statistically significant difference between levosimendan and dobutamine in all-cause mortality at 180 days {Hazard Ratio = 0.91 (95% CI [0.74, 1.13] p-value 0.401)}. However, there was a numerical advantage in mortality at Day 5 (4% levosimendan vs. 6% dobutamine) for levosimendan. This advantage persisted through the 31-day period (12% levosimendan vs. 14% dobutamine) and was most prominent in those individuals who received baseline beta-blocker therapy. In both treatment groups, patients with low baseline blood pressure experienced higher rates of mortality than did those with higher baseline blood pressure.

LIDO

Levosimendan has been shown to lead to dose-dependent increases in cardiac output and stroke volume as well as dose-dependent decrease in pulmonary capillary wedge pressure, mean arterial pressure and total peripheral resistance.

In a double-blind multicentre trial, 203 patients with severe low output heart failure (ejection fraction ≤0.35, cardiac index <2.5 L/min/m², pulmonary capillary wedge pressure (PCWP) >15 mmHg) and in need of inotropic support received levosimendan (loading dose 24 μg/kg over 10 minutes followed by a continuous infusion of 0.1-0.2 μg/kg/min) or dobutamine (5-10 μg/kg/min) for 24 hours. The aetiology of heart failure was ischaemic in 47% of the patients; 45% had idiopathic dilative cardiomyopathy. 76% of the patients had dyspnoea at rest. Major exclusion criteria included systolic blood pressure below 90 mmHg and heart rate above 120 beats per minute. The primary endpoint was an increase in cardiac output by ≥30% and a simultaneous decrease of PCWP by ≥25% at 24 hours. This was reached in 28% of levosimendan treated patients compared with 15% after dobutamine treatment (p=0.025). Sixty-eight percent of symptomatic patients had an improvement in their dyspnoea scores after levosimendan treatment, compared with 59% after dobutamine treatment. Improvement in fatigue scores were 63% and 47% after levosimendan and dobutamine treatment, respectively. All-cause 31-day mortality was 7.8% for levosimendan and 17% for dobutamine treated patients.

RUSSLAN

In a further double-blind multicentre trial carried out primarily to evaluate safety, 504 patients with decompensated heart failure after acute myocardial infarction who were assessed to require inotropic support were treated with levosimendan or placebo for 6 hours. There were no significant differences in the incidence of hypotension and ischaemia between the treatment groups.

No adverse effect on survival up to 6 months was observed in a retrospective analysis of the LIDO and RUSSLAN trials.

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