Stangier Joachim, Eriksson Bengt I, Dahl Ola E, Ahnfelt Lennart, Nehmiz Gerhard, Stähle Hildegard, Rathgen Karin, Svärd Robbyna
Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH and Co KG, Birkendorfer Strasse, Biberach an der Riss, D-88397, Germany.
J Clin Pharmacol. 2005 May;45(5):555-63. doi: 10.1177/0091270005274550.
Dabigatran etexilate is an oral low-molecular-weight direct thrombin inhibitor. Following oral administration, dabigatran etexilate is rapidly converted to its active form, dabigatran. The authors investigated the absorption, distribution, and elimination of a single 150-mg dose capsule formulation of dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. In an open-label, 3-way crossover study, dabigatran etexilate was administered to 18 male volunteers in the fasted state, after administration of food and with coadministration of the proton pump inhibitor, pantoprazole. In a subsequent multicenter, open-label study, 59 patients received a single dose of dabigatran etexilate, administered 1 to 3 hours following total hip replacement. In healthy volunteers, food had no effect on the extent of absorption of dabigatran etexilate, although there was reduced interindividual variability for dabigatran maximum plasma concentration and AUC(0-infinity). A decrease in the mean dabigatran AUC(0-infinity) (904 to 705 ng*h/mL) occurred with coadministration of pantoprazole. In patients undergoing total hip replacement, immediate onset of absorption was seen with the maximum plasma concentration of dabigatran occurring after 6 hours. The AUC(0-24) of dabigatran was 88% of the steady-state AUC using a preliminary tablet formulation and 106% of that seen in the healthy volunteer study. Compared with healthy volunteers, the postoperative profile was flattened with delayed peak concentrations. In summary, administration of the dabigatran etexilate capsule with food has no effect on the extent of dabigatran absorption, with a moderate decrease when coadministered with pantoprazole. Adequate plasma concentrations of dabigatran were seen with early postoperative administration of the dabigatran etexilate capsule. These pharmacokinetic characteristics confirm the suitability of this oral solid dosage form for use in future clinical trials.
达比加群酯是一种口服低分子量直接凝血酶抑制剂。口服给药后，达比加群酯迅速转化为其活性形式达比加群。作者研究了150毫克单剂量胶囊制剂的达比加群酯在健康志愿者和接受全髋关节置换术患者中的吸收、分布和消除情况。在一项开放标签、三交叉研究中，达比加群酯在禁食状态下、进食后以及与质子泵抑制剂泮托拉唑合用时给予18名男性志愿者。在随后的一项多中心、开放标签研究中，59名患者在全髋关节置换术后1至3小时接受了单剂量的达比加群酯。在健康志愿者中，食物对达比加群酯的吸收程度没有影响，尽管达比加群的最大血浆浓度和AUC(0-无穷大)的个体间变异性有所降低。泮托拉唑合用时，达比加群的平均AUC(0-无穷大)有所下降(从904降至705纳克·小时/毫升)。在接受全髋关节置换术的患者中，吸收立即开始，达比加群的最大血浆浓度在6小时后出现。使用初步片剂制剂时，达比加群的AUC(0-24)为稳态AUC的88%，在健康志愿者研究中为106%。与健康志愿者相比，术后曲线变平，峰值浓度延迟。总之，达比加群酯胶囊与食物一起给药对达比加群的吸收程度没有影响，与泮托拉唑合用时会有适度降低。术后早期给予达比加群酯胶囊可使达比加群达到足够的血浆浓度。这些药代动力学特征证实了这种口服固体剂型适用于未来的临床试验。
