Teng Renli, Sarich Troy C, Eriksson Ulf G, Hamer Jennifer E, Gillette Stephen, Schützer Kajs-Marie, Carlson Glenn F, Kowey Peter R
Experimental Medicine, AstraZeneca LP, FOC SW1-724, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE 19850-5437, USA.
J Clin Pharmacol. 2004 Sep;44(9):1063-71. doi: 10.1177/0091270004268446.
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.
口服直接凝血酶抑制剂希美加群正被开发用于预防和治疗血栓栓塞。这项单盲、随机、安慰剂对照、平行组研究调查了希美加群（每12小时36毫克，共8天，以其血液中的活性形式美拉加群计量）与胺碘酮（第4天单次口服600毫克剂量）在健康男性受试者（n = 26）中相互作用的可能性。对于胺碘酮+希美加群与胺碘酮+安慰剂，胺碘酮AUC(0 - 120)和C(max)的几何平均比值（90%置信区间）分别为0.87（0.69 - 1.08）和0.86（0.66 - 1.11）。对于胺碘酮的主要代谢产物去乙基胺碘酮，AUC(0 - 120)的相应比值为1.00（0.89 - 1.12），C(max)的相应比值为0.92（0.77 - 1.09）。希美加群+胺碘酮与希美加群相比，美拉加群AUC(0 - 12)的几何平均比值（90%置信区间）为1.21（1.17 - 1.25），美拉加群C(max)的几何平均比值为1.23（1.18 - 1.28）。这些置信区间在区间内或仅略超出区间，表明无相互作用（胺碘酮对美拉加群的作用为0.8 - 1.25，美拉加群对胺碘酮或去乙基胺碘酮的作用为0.7 - 1.43）。胺碘酮不影响美拉加群对活化部分凝血活酶时间的浓度 - 效应关系。希美加群与单剂量胺碘酮合用时耐受性良好。需要对该联合用药的安全性进行评估，以确认本研究中相对较小的药代动力学变化无临床意义。
