A Pharmacokinetic Study of the Combined Administration of Amiodarone and Ximelagatran, an Oral Direct Thrombin Inhibitor

Abstract

The oral direct thrombin inhibitor ximelagatran is being developed for the prevention and treatment of thromboembolism. This single‐blind, randomized, placebo‐controlled, parallel‐group study investigated the potential for the interaction of ximelagatran (36 mg every 12 hours for 8 days, measured as its active form melagatran in blood) and amiodarone (single 600‐mg oral dose on day 4) in healthy male subjects (n = 26). For amiodarone + ximelagatran versus amiodarone + placebo, geometric mean ratios (90% confidence intervals for amiodarone AUC_0–120 and C_max were 0.87 (0.69–1.08) and 0.86 (0.66–1.11), respectively. For desethylamiodarone, the principal metabolite of amiodarone, the corresponding ratios were 1.00 (0.89–1.12) for AUC_0–120 and 0.92 (0.77–1.09) for C_max. The geometric mean ratios (90% confidence intervals) for ximelagatran + amiodarone versus ximelagatran were 1.21 (1.17–1.25) for melagatran AUC_0–12 and 1.23 (1.18–1.28) for melagatran C_max. These confidence intervals were within or only slightly outside the interval, suggesting no interaction (0.8–1.25 for the effect of amiodarone on melagatran and 0.7–1.43 for the effect of melagatran on amiodarone or desethylamiodarone). Amiodarone did not affect the concentration‐effect relationship of melagatran on activated partial thromboplastin time. Ximelagatran was well tolerated when coadministered with a single dose of amiodarone. Evaluation of the safety of the combination is needed to confirm that the relatively small pharmacokinetic changes in this study are of no clinical significance.