Vitamin K antagonists including
warfarin are associated with numerous interactions with other drugs and foods. In clinical practice, this complicates the task of maintaining plasma levels of
warfarin within a narrow therapeutic window and so maximizing protection against thromboembolic events while minimizing the risk of complications, particularly
bleeding. In contrast,
ximelagatran has a low potential for pharmacokinetic
drug:
drug and food interactions. There is no significant metabolism of
melagatran, and the main route of elimination of
melagatran is renal excretion that appears to occur via glomerular filtration. Most importantly,
cytochrome P450 isoenzymes that mediate many
drug:drug interactions are not involved in the biotransformation of
ximelagatran to
melagatran. No significant pharmacokinetic interactions have been observed when oral
ximelagatran is administered with a range of agents, including
diclofenac,
diazepam,
nifedipine,
digoxin,
atorvastatin, or
amiodarone. The low potential for
drug:drug interactions with
ximelagatran is also supported by an analysis of the pharmacokinetic data from clinical studies in patients with
atrial fibrillation receiving long-term treatment with oral
ximelagatran. Increases of mean
melagatran area under the curve and maximum plasma concentration ( Cmax) of up to approximately 80% have been observed when
ximelagatran is co-administered with the
macrolide antibiotics erythromycin or
azithromycin, and the mechanism for this interaction is currently under investigation. The bioavailability of
melagatran is not altered by co-administration with food or alcohol. The
melagatran-induced prolongation of activated partial thromboplastin time (APTT), an ex vivo coagulation time assay used as a measure of
thrombin inhibition, is not altered by other drugs [including
digoxin,
atorvastatin,
acetylsalicylic acid (ASA), and
amiodarone], food, or alcohol. The effect of
melagatran on capillary bleeding time, which is prolonged as a result of the inhibition of
thrombin-induced platelet aggregation, is relatively low and additive to the platelet-inhibitory effect of ASA.