Pharmacokinetic and pharmacodynamic interactions between the novel calciumsensitiser levosimendan and warfarin

Objective: To study the effects of possible interactions between levosimend an 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 u sed. During one phase, levosimendan (0.5 mg four times daily) was given ora lly to ten healthy subjects for 9 days. On the fourth treatment day with le vosimendan, a single oral dose of warfarin (25 mg) was given. Pharmacokinet ic parameters of levosimendan from the third and fourth treatment days were compared with each other. During the other treatment phase the subjects re ceived only a single dose of warfarin. Pharmacokinetic parameters of warfar in alone were compared with those determined after concomitant administrati on 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 shorte r after concomitant levosimendan administration than after warfarin alone. However, concomitant levosimendan administration did not potentiate the eff ects of warfarin on blood coagulation assessed using activated partial thro mboplastin 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 administra tion. Continuous treatment with oral levosimendan caused headache, which wa s 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.