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A pharmacokinetic study of the combined administration of amiodarone and ximelagatran, an oral direct thrombin inhibitor.

Author(s): Teng R, Sarich TC, Eriksson UG, Hamer JE, Gillette S, Schutzer KM, Carlson GF Jr, Kowey PR

Affiliation(s): Experimental Medicine, AstraZeneca LP, FOC SW1-724, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE 19850-5437, USA.

Publication date & source: 2004-09, J Clin Pharmacol., 44(9):1063-71.

Publication type: Clinical Trial; Randomized Controlled Trial

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.

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