Saila Antila

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

OBJECTIVE Levosimendan is a new calcium sensitizer with additional vasodilatory properties developed for the short-term intravenous treatment of congestive heart failure. The aims of the present study were to determine the pharmacokinetics and hemodynamic effects of levosimendan and its metabolites during and after a 24-hour levosimendan infusion. METHODS The study was an open-label, non-randomized, phase II study in 2 centers. Twelve patients with NYHA III-IV heart failure received 0.2 microg/kg/min continuous infusion of levosimendan for 24 hours. Blood samples for the determination of plasma concentrations of the parent drug and the metabolites were drawn repeatedly during the infusion and the 2-week follow-up period. Heart rate from Holter recordings and blood pressure were measured. RESULTS The elimination half-life of levosimendan was 1.3 hours and that of the metabolites 75-78 hours. The mean maximum increase in heart rate of 10 bpm (p < 0.005) and the mean maximum decreases in systolic and diastolic blood pressure of 12 mmHg and 8 mmHg (p < 0.05 for both), respectively, were observed during the first day after stopping levosimendan infusion. The hemodynamic effects slowly declined during the follow-up, and after 1 week no statistically significant differences compared with baseline were observed. No increase in ventricular arrhythmias was seen. CONCLUSION A 24-hour infusion of levosimendan induces hemodynamic effects lasting several days after stopping the infusion. The prolongation of the effects beyond the infusion period is most likely due to an active metabolite with a long half-life.

Pharmacokinetics of levosimendan in healthy volunteers and patients with congestive heart failure.

Levosimendan is a new inodilatory agent that sensitizes troponin-C in heart muscle cells to calcium, thus improving contractility. The pharmacokinetics of levosimendan were evaluated using a double-isotope technique in eight healthy volunteers and in eight patients with mild congestive heart failure (CHF). A single i.v. dose of 0.50 mg 14C-labeled levosimendan and a single oral dose of 0.50 mg 13C15N-labeled levosimendan were administered concomitantly. The elimination half-lives (mean +/- SD) of levosimendan were 0.96 +/- 0.16 h in healthy volunteers and 1.03 +/- 0.11 h in patients. The respective figures for total drug were 5.73 +/- 1.53 h and 5.23 +/- 0.99 h. Clearances of levosimendan averaged 359 +/- 69 ml/min in healthy volunteers and 296 +/- 61 ml/min in patients and of total drug 104 +/- 15 and 85 +/- 20 ml/min, respectively. Volumes of distribution at steady state were for levosimendan 21.9 +/- 5.9 L in healthy volunteers and 19.5 +/- 4.5 L in patients and for 14C-drug 27.9 +/- 5.3 L and 23.8 +/- 2.8 L, respectively. The bioavailability of oral levosimendan was 85 +/- 6% in healthy volunteers and 84 +/- 4% in patients.

Clinical Pharmacology of Levosimendan

Levosimendan has been developed for the treatment of decompensated heart failure and is used intravenously when patients with heart failure require immediate initiation of drug therapy. It increases cardiac contractility and induces vasodilatation.The pharmacokinetics of levosimendan are linear at the therapeutic dose range of 0.05–0.2 μg/kg/minute. The short half-life (about 1 hour) of the parent drug, levosimendan, enables fast onset of drug action, although the effects are long-lasting due to the active metabolite OR-1896, which has an elimination half-life of 70–80 hours in patients with heart failure (New York Heart Association functional class III-IV).Although levosimendan is administered intravenously, it is excreted into the small intestine and reduced by intestinal bacteria to an amino phenolpyridazinone metabolite (OR-1855). This metabolite is further metabolised by acetylation to N-acetylated conjugate (OR-1896). The circulating metabolites OR-1855 and OR-1896 are formed slowly, and their maximum concentrations are seen on average 2 days after stopping a 24-hour infusion. The haemodynamic effects after levosimendan seem to be similar between fast and slow acetylators despite the fact that the enzyme N-acetyltransferase-2, which is responsible for the metabolism of OR-1855 to OR-1896, is polymorphically distributed in the population.Levosimendan reduces peripheral vascular resistance and has direct contractility-enhancing effects on the failing left ventricle. It also improves indices of diastolic function and seems to improve the function of stunned myocardium. Despite an improvement in ventricular function, levosimendan does not increase myocardial oxygen uptake significantly. An increase in coronary blood flow and a reduction in coronary vascular resistance have been observed. Levosimendan reduces plasma brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels substantially, and a decrease in plasma endothelin-1 has been observed. Levosimendan also exerts beneficial effects on proinflammatory cytokines and apoptosis mediators. The effects of a 24-hour levosimendan infusion on filling pressure, ventricular function and BNP, as well as NT-proBNP, last for at least 7 days.

Pharmacokinetics and Pharmacodynamics of Intravenous Inotropic Agents

Positive inotropic drugs have various mechanisms of action. Long-term use of cyclic adenosine monophosphate (cAMP)-dependent drugs has adverse effects on the prognosis of heart failure patients, whereas digoxin has neutral effect on mortality. There are, however, little data on the effects of intravenous inotropic drugs on the outcome of patients.Intravenous inotropic agents are used to treat cardiac emergencies and refractory heart failure. β-Adrenergic agonists are rapid acting and easy to titrate, with short elimination half-life. However, they increase myocardial oxygen consumption and are thus hazardous during myocardial ischaemia. Furthermore they may promote myocyte apoptosis. Phosphodiesterase (PDE) III inhibiting drugs (amrinone, milrinone and enoximone) increase contractility by reducing the degradation of cAMP. In addition, they reduce both preload and afterload via vasodilation. Short-term use of intravenous milrinone is not associated with increased mortality, and some symptomatic benefit may be obtained when it is used in refractory heart failure. Furthermore, PDE III inhibitors facilitate weaning from the cardiopulmonary bypass machine after cardiac surgery.Levosimendan belongs to a new group of positive inotropic drugs, the calcium sensitisers. It has complex pharmacokinetics and long-lasting haemodynamic effects as a result of its active metabolites. In comparative trials, it has been better tolerated than the most widely used β-agonist inotropic drug, dobutamine.The pharmacokinetics of the intravenous inotropic drugs might sometimes greatly modify and prolong the response to the therapy, for example because of long-acting active metabolites. These drugs display considerable differences in their pharmacokinetics and pharmacodynamics, and the selection of the most appropriate inotropic drug for each patient should be based on careful consideration of the clinical status of the patient and on the pharmacology of the drug.

Site dependent bioavailability and metabolism of levosimendan in dogs

Site specific bioavailability and metabolism of levosimendan was studied in ten dogs by placing intestinal access port catheters in different parts of the gastrointestinal tract. 14C-labelled levosimendan (0.1 mg/kg) was administered intravenously, by gastric tube and directly through catheters that were placed in the duodenum, jejunum and ileum. Plasma samples were collected and radioactivity in the different organs and tissues was measured. The results of the present study showed that bioavailability of levosimendan was high varying from 71 to 86% after extravascular administration. Metabolite OR-1855 concentrations in the plasma were about 3-4 times higher after administration to the ileum compared to the other administration routes. It can be concluded that the bioavailability of levosimendan is not affected by site specific administration. The bacteria or enzymes responsible for the metabolism of levosimendan are located in the lower parts of the gastrointestinal tract.

Pharmacodynamics and Pharmacokinetics of Oral Levosimendan and Its Metabolites in Patients With Severe Congestive Heart Failure: A Dosing Interval Study

The objective of this study was to explore the pharmacodynamics and pharmacokinetics of oral levosimendan in patients with severe congestive heart failure. This was a randomized, parallel‐group, double‐blind, placebo‐controlled trial. Oral levosimendan 2 to 8 mg daily or placebo was administered to 25 patients with New York Heart Association class III–IV congestive heart failure for 4 weeks. Pharmacodynamic variables consisted of heart rate‐corrected electromechanical systole, heart rate, and systolic and diastolic blood pressure. The pharmacokinetics of levosimendan and its metabolites, OR‐1855 and OR‐1896, was assessed. The 4‐ to 8‐mg daily doses of oral levosimendan showed moderate inotropic effects. Blood pressure remained unchanged with all doses. A moderate increase in heart rate was observed except with the 2‐mg dose. Pharmacokinetic parameters of the metabolites increased linearly with the dose (P .002 for Cmax and AUC0–8h for both treatment groups). It was concluded that oral levosimendan has inotropic and chronotropic effects in patients with severe congestive heart failure. Plasma concentrations of its metabolites increase dose dependently.

Haemodynamic interactions of a new calcium sensitizing drug levosimendan and captopril.

AbstractObjective: Levosimendan in a new inodilator drug that sensitises troponin C in heart muscle cells to calcium, thus improving contractility. In previous studies, a single 2 mg intravenous dose of levosimendan increased cardiac output (CO) in healthy volunteers by about 40% and decreased pulmonary capillary wedge pressure in heart failure patients by 40–50%.The aim of the present, double-blind study was to evaluate the safety of concomitant use of levosimendan and an ACE-inhibiting drug. Methods: The haemodynamic effects of levosimendan, given with or without captopril, were evaluated by using 2-dimensional echocardiography, repeated blood pressure measurements and by ambulatory ECG recordings. Twenty-four male patients with stable NYHA II-III heart failure (EF<40%) after a previous myocardial infarct were given, in randomised order, a single IV infusion of levosimendan or placebo. The infusions were repeated after 2 weeks treatment with upto 50 mg b.i.d. of captopril. Twelve patients received levosimendan 1 mg and twelve received 2 mg. Results: Mean CO was increased from 6.0 to 6.81·min−1 in patients receiving 1 mg levosimendan compared to placebo, but only from 6.3 to 6.51·min−1 in patients receiving 2 mg. The increase in CO was statistically significant when all levosimendan patients were compared to placebo. Heart rate did not change after either dose. Mean stroke volume increased significantly after 1 mg but not after 2 mg of levosimendan. The addition of captopril did not change the effects of levosimendan. No additional decrease in systolic or diastolic blood pressure was observed when levosimendan and captopril were given concomitantly. Conclusion: It seems that concomitant treatment with captopril does not change the haemodynamic effects of levosimendan. No adverse haemodynamic interactions were seen.

Transdermal delivery of levosimendan

The aim of this study was to determine if transdermal penetration of levosimendan, a novel positive inotropic drug, could be enhanced and controlled by formulation modifications. Penetration of levosimendan across human epidermis in vitro was determined using abdominal excised skin and diffusion cells. Predicted steady-state plasma concentrations of levosimendan were estimated using permeabilities and pharmacokinetic parameters of levosimendan. For penetration enhancement we used different pH values, co-solvents, cyclodextrins, surfactants, penetration enhancers, liposomes, and iontophoresis. Sodium lauryl sulfate, ethanol, oleic acid, and soya phosphatidylcholine or their combinations clearly increased levosimendan permeation across the skin in vitro. Iontophoresis was also an efficient method to increase transdermal permeation of levosimendan. A hydrophilic co-solvent/penetration enhancer is needed to achieve better permeability of levosimendan across the skin. In conclusion, transdermal delivery of levosimendan can be significantly increased by formulation modification. Based on kinetic calculations, therapeutic plasma concentrations may be achievable transdermally.

Pharmacodynamic interactions of levosimendan and felodipine in patients with coronary heart disease.

AbstractObjective: The aim was to study the pharmacodynamic interactions and safety of the co-administration of the calcium sensitizer levosimendan and the calcium antagonist felodipine in patients with coronary heart disease (CHD) and with normal ejection fraction (EF). Methods: The study was a randomized, double blind, placebo-controlled, crossover study in 24 male patients with Canadian Cardiovascular Society (CCS) class II CHD, consisting of four treatment periods, each period lasting for 7–10 days. In the first period the patients received either oral levosimendan (LS) (0.5 mg) or placebo (PL) four times daily and were then crossed over to the other therapy for the second and third period. After the third period the patients were changed back to the therapy administered in the first period. Open label felodipine (FD), 5 mg once daily, was co-administered on the third and fourth treatment period. Differences between the four treatments (LS, PL, FD and LS + FD) in systolic time intervals, exercise capacity, heart rate, blood pressure and 24-hour continuous electrocardiography (Holter) were assessed. Results: The differences between treatments regarding heart rate corrected electromechanical systole (QS2i), pre-ejection period (PEP) and heart rate corrected left ventricular ejection time (LVETi) were significant (p < 0.001, p < 0.001 and p = 0.004, respectively). Levosimendan shortened QS2i by 10 ms (95% CI [−15, −4]), PEP by 6 ms (95% CI [−10, −3]) and LVETi by 7 ms (95% CI [−13, −2]) compared with placebo, indicating a moderate positive inotropic effect. The results were similar, when levosimendan was administered concomitantly with felodipine. Levosimendan did not significantly change systolic blood pressure and no potentation of response was seen with concomitant administration with felodipine. The increase in heart rate after levosimendan and its combination with felodipine was equal (6–7 bpm). There was no difference in mean cumulative exercise time between the treatments. The combination of levosimendan and felodipine was well tolerated. Conclusion: No clinically significant pharmacodynamic interactions between levosimendan and felodipine were seen. Levosimendan did not aggravate myocardial ischemia. Levosimendan can safely be administered to patients with CHD together with a dihydropyridine calcium antagonist.