Pharmacokinetic-pharmacodynamic interrelationships of intravenous and oral levosimendan in patients with severe congestive heart failure.
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 microg/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 (Holter).


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.
Põder
P
P
Cardiovascular Projects, Research Centre, Orion Pharma, Espoo, Finland. pentti.poder@orionpharma.com
Eha
J
J
Sundberg
S
S
Antila
S
S
Heinpalu
M
M
Loogna
I
I
Planken
U
U
Rantanen
S
S
Lehtonen
L
L
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects*; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D011724:Pyridazines / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D000077464:Simendan; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan