No clinically significant interactions between the oral direct thrombin inhibitor ximelagatran and amiodarone, atorvastatin, or digoxin

Abstract

Background The oral direct thrombin inhibitor ximelagatran has shown clinical benefit in patients with atrial fibrillation at risk of stroke. The potential for interaction of ximelagatran with amiodarone, atorvastatin, or digoxin, was assessed in 3 randomized studies in healthy volunteers. Methods: Study 1 was a placebo-controlled, parallel-group study (n=26) with ximelagatran (36mg) or placebo BID for 8 days and amiodarone (single 600mg oral dose) on Day 4. Study 2 was a crossover study (n=16) with atorvastatin (single 40mg oral dose) during one treatment period and ximelagatran (36mg BID for 5 days) plus a single dose of atorvastatin (40mg) on Day 4 during the other treatment period. Study 3 was a double-blind, crossover study (n=16) with ximelagatran (36mg) or placebo BID for 8 days and digoxin (single 0.5mg dose) on Day 4. Results: For melagatran, the active form of ximelagatran, AUC and Cmax geometric mean ratios (90% CI) for combined therapy relative to monotherapy with either drug were within or only slightly outside predefined bounds for no interaction. Similarly, no relevant changes were observed for the AUC and Cmax of amiodarone, atorvastatin, or digoxin. None of the coadministered drugs affected the concentration–effect relationship of melagatran on activated partial thromboplastin time. Conclusions: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when ximelagatran was administered with amiodarone, atorvastatin, or digoxin. Clinical Pharmacology & Therapeutics (2004) 75, P78–P78; doi: 10.1016/j.clpt.2003.11.294