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-depend ently on cardiac troponin C. In the present study pharmacokinetic-pharmacod ynamic interrelations of levosimendan were assessed. Subjects and methods: Ten healthy subjects (22 - 27 years) were given single doses of 2 mg of lev osimendan in 4 different formulations: intravenous (i.v.), conventional tab let (CT), conventional capsule (CC), and slow-release tablet (SR) on differ ent days. Systolic time intervals and impedance cardiography were recorded up to 4 hours post drug. Plasma concentrations of levosimendan and its meta bolite OR-1855 were analyzed using HPLC. Hysteresis loops were constructed by connecting the effect-concentration points in time order. In addition, p harmacokinetic-pharmacodynamic modelling was performed with the i.v, data. Results: The i.v. administration, giving a maximal levosimendan concentrati on 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 co nventional oral formulations (giving maximal drug concentrations of about 7 0 - 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 re sulted in low drug concentrations and generally weaker effects than the oth er formulations. The bioavailability of CT and CC was 83 and 87%, while tha t of SR was only 31%. QS2i showed counter-clockwise hysteresis after all fo rmulations (p < 0.01). The mean equilibration half-time (In(2)/ke(0)) after i.v. administration was 9.6 min. Only after SR, OR-1855 was detected in ap preciable amounts in plasma, the highest value being 2.2 ng x ml(-1) which occurred 24 hours after drug intake. Conclusion: In conclusion, the pharmac okinetic-dynamic behavior of the inotropy index QS2i indicates an equilibra tion delay of levosimendan, which most probably reflects the time the drug requires to distribute from plasma to its cardiac site of action. The devia nt kinetic-dynamic profile of the oral slow-release formulation suggests a different absorption pattern of levosimendan from this formulation.