Pharmacokinetic-pharmacodynamic interrelationships of intravenous and oral levosimendan in patients with severe congestive heart failure
Põder, P.; Eha, J.; Sundberg, S.; Antila, S.; Heinpalu, M.; Loogna, I.; Planken, U.; Rantanen, S.; Lehtonen, L.
International Journal of Clinical Pharmacology and Therapeutics 41(8): 365-373
2003
ISSN/ISBN: 0946-1965 PMID: 12940594 Document Number: 556245
Objective: To assess the pharmacokinetic-pharmacodynamic (PK-PD) interrelations after a 6-hour continuous infusion and a 2 mg single oral dose of levosimendan in patients with congestive heart failure (CHF). Methods: This was an open-label, non-randomized Phase II trial in 29 patients with New York Heart Association (NYHA) class III-IV CHF, comprising 2 study days. On the first day, patients were given 6-hour levosimendan infusion with the dose 0.2 mug/kg/min. After a 1-week washout, the patients received a 2 mg single oral dose of levosimendan. Heart rate-corrected electromechanical systole QS2i was the primary variable. Secondary variables were heart rate (HR), systolic (sBP) and diastolic blood pressure (dBP) and 24-hour ambulatory ECG (Holier). Results: QS2i shortened from 515 ms at baseline to 506 ms at the end of 6-hour infusion (p=0.007). After 2 mg single dose, QS2i shortened at 2 h after drug intake from 532 ms at baseline to 525 ms (p=0.006). The effect was similar also at 8 h (532 ms vs 526 ms, p=0.017). Mean of maximum shortening of QS2i observed during the infusion was 22 ms (p<0.0001) and 17 ms after 2 mg single oral dose (p<0.0001). The concentration-effect loops for QS2i showed a clear counter-clockwise hysteresis with both modes of administration. sBP and dBP decreased both during infusion and after 2 mg oral dose. HR remained unchanged during both modes of administration. Conclusions: Both 6-hour infusion and 2 mg single dose of levosimendan showed that levosimendan possesses moderate inotropic and vasodilatory effects in patients with severe congestive heart failure, which could be described as counter-clockwise hysteresis. It seemed that the vasodilatory effect appeared earlier than the inotropic effect.