Pharmacokinetic and pharmacodynamic interactions between the novel calcium sensitiser levosimendan and warfarin.
OBJECTIVE
To study the effects of possible interactions between levosimendan and warfarin on pharmacokinetics and pharmacodynamics. Furthermore, the effects of levosimendan on blood coagulation were investigated.


METHODS
Open, randomised cross-over design with two treatment phases was used. During one phase, levosimendan (0.5 mg four times daily) was given orally to ten healthy subjects for 9 days. On the fourth treatment day with levosimendan, a single oral dose of warfarin (25 mg) was given. Pharmacokinetic parameters of levosimendan from the third and fourth treatment days were compared with each other. During the other treatment phase the subjects received only a single dose of warfarin. Pharmacokinetic parameters of warfarin alone were compared with those determined after concomitant administration of levosimendan. Changes in blood coagulation parameters were evaluated after levosimendan and warfarin alone and after concomitant administration.


RESULTS
Warfarin did not change the pharmacokinetics of levosimendan. The distribution volume of warfarin was higher and elimination half-life shorter after concomitant levosimendan administration than after warfarin alone. However, concomitant levosimendan administration did not potentiate the effects of warfarin on blood coagulation assessed using activated partial thromboplastin time (APTT) and thromboplastin time (TT-SPA). Levosimendan alone for 3 days did not change APTT or TT-SPA values. There were no changes in the protein binding of levosimendan or warfarin upon concomitant administration. Continuous treatment with oral levosimendan caused headache, which was probably due to cerebral vasodilation.


CONCLUSIONS
Concomitant levosimendan administration did not potentiate the effect of warfarin on blood coagulation after a single dose. Levosimendan itself had no effects on blood coagulation.
Antila
S
S
Orion Pharma, Research Centre, Espoo, Finland. saila.antila@orion.fi
Jarvinen
A
A
Honkanen
T
T
Lehtonen
L
L
D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001777:Blood Coagulation / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D018592:Cross-Over Studies; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D010314:Partial Thromboplastin Time; D011485:Protein Binding; D011724:Pyridazines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077464:Simendan; D014859:Warfarin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D000925:Anticoagulants; D001798:Blood Proteins; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan; D014859:Warfarin