S. Antila et al., Pharmacokinetic and pharmacodynamic interactions between the novel calciumsensitiser levosimendan and warfarin, EUR J CL PH, 56(9-10), 2000, pp. 705-710
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.