Integrated pharmacokinetics and pharmacodynamics of the novel calcium sensitizer levosimendan as assessed by systolic time intervals.

BACKGROUND: Levosimendan is a new calcium sensitizer, acting calcium-dependently on cardiac troponin C. In the present study pharmacokinetic-pharmacodynamic interrelations of levosimendan were assessed. SUBJECTS AND METHODS: Ten healthy subjects (22-27 years) were given single doses of 2 mg of levosimendan in 4 different formulations: intravenous (i.v.), conventional tablet (CT), conventional capsule (CC), and slow-release tablet (SR) on different days. Systolic time intervals and impedance cardiography were recorded up to 4 hours post drug. Plasma concentrations of levosimendan and its metabolite OR-1855 were analyzed using HPLC. Hysteresis loops were constructed by connecting the effect-concentration points in time order. In addition, pharmacokinetic-pharmacodynamic modelling was performed with the i.v. data. RESULTS: The i.v. administration, giving a maximal levosimendan concentration of 180 ng x ml(-1), increased heart rate by 8 beats min(-1) and cardiac output by 18%. It shortened heart rate corrected electromechanical systole QS2i by 23 ms, indicating a fairly strong positive inotropic effect. The conventional oral formulations (giving maximal drug concentrations of about 70-80 ng x ml(-1)) increased heart rate by 4-5 beats min(-1) and cardiac output by 5-8%, while QS2i shortened by 9-13 ms. The SR formulation resulted in low drug concentrations and generally weaker effects than the other formulations. The bioavailability of CT and CC was 83 and 87%, while that of SR was only 31%. QS2i showed counter-clockwise hysteresis after all formulations (p < 0.01). The mean equilibration half-time (ln(2)/k(e0)) after i.v. administration was 9.6 min. Only after SR, OR-1855 was detected in appreciable amounts in plasma, the highest value being 2.2 ng x ml(-1) which occurred 24 hours after drug intake. CONCLUSION: In conclusion, the pharmacokinetic-dynamic behavior of the inotropy index QS2i indicates an equilibration delay of levosimendan, which most probably reflects the time the drug requires to distribute from plasma to its cardiac site of action. The deviant kinetic-dynamic profile of the oral slow-release formulation suggests a different absorption pattern of levosimendan from this formulation.

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.

Haemodynamic dose-efficacy of levosimendan in healthy volunteers.

Levosimendan is a new calcium-sensitiser intended for the treatment of congestive heart failure. The results of preclinical studies indicate it has positive inotropic and vasodilator effects. In the open study reported here up to 5 mg levosimendan and vehicle were administered to 8 healthy male volunteers at one- to 2-week intervals. Efficacy was evaluated using M-mode echocardiography, and by measuring systolic time intervals, recording ECG and measuring blood pressure. For almost all haemodynamic parameters except heart rate (HR) the maximum effect was seen 10 or 20 min after drug infusion. Effects 10 min after infusion of drug and vehicle were compared. HR was significantly increased 10 min only after infusion of 5 mg: significant increases were seen 60 min after infusions of 2, 3 and 5 mg (4, 8 and 17 beats.min-1, respectively). Diastolic blood pressure was significantly lower after doses of 1 mg or more. The decrease after 5 mg was 17 mmHg. Systolic blood pressure tended to increase. Fractional shortening (FS) and ejection fraction (EF) increased significantly after doses of 1 mg and higher. EF 10 min after infusion of vehicle was 54%. It increased to 73% after 5 mg. Decreases in electromechanical systole (QS2i) 10 min after 2, 3 and 5 mg were significant. There were no clinically significant adverse events or changes in laboratory safety values. The changes in QS2i, FS, EF and blood pressure indicate that levosimendan has positive inotropic and vasodilator effects in healthy subjects.