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

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Abstract
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.

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