Schützer Kajs-Marie, Wall Ulrika, Lönnerstedt Carina, Ohlsson Lis, Teng Renli, Sarich Troy C, Eriksson Ulf G
AstraZeneca R&D Mölndal, Mölndal, Sweden.
Curr Med Res Opin. 2004 Mar;20(3):325-31. doi: 10.1185/030079903125003035.
To investigate whether crushed or dissolved tablets of the oral direct thrombin inhibitor ximelagatran are bioequivalent to whole tablet administration. Ximelagatran is currently under development for the prevention and treatment of thromboembolic disorders.
This was an open-label, randomised, three-period, three-treatment crossover study in which 40 healthy volunteers (aged 20-33 years) received a single 36-mg dose of ximelagatran administered in three different ways: I swallowed whole, II crushed, mixed with applesauce and ingested and III dissolved in water and administered via nasogastric tube.
The plasma concentrations of ximelagatran, its intermediates and the active form melagatran were determined. Ximelagatran was rapidly absorbed and the bioavailability of melagatran was similar after the three different administrations, fulfilling the criteria for bioequivalence. The mean area under the plasma concentration-versus-time curve (AUC) of melagatran was 1.6 micromol.h/L (ratio 1.01 for treatment II/I and 0.97 for treatment III/I), the mean peak concentration (C(max)) was 0.3 micromol/L (ratio 1.04 for treatment II/I and 1.02 for treatment III/I) and the mean half-life (t(1/2)) was 2.8 h for all treatments. The time to C(max) (t(max)) was 2.2h for the whole tablet and approximately 0.5 h earlier when the tablet was crushed or dissolved (1.7-1.8 h), due to a more rapid absorption. The study drug was well tolerated as judged from the low incidence and type of adverse events reported.
The present study showed that the pharmacokinetics (AUC and C(max)) of melagatran were not significantly altered whether ximelagatran was given orally as a crushed tablet mixed with applesauce or dissolved in water and given via nasogastric tube.
研究口服直接凝血酶抑制剂希美加群的碾碎片或溶解片与整片给药是否生物等效。希美加群目前正处于研发阶段，用于预防和治疗血栓栓塞性疾病。
这是一项开放标签、随机、三周期、三治疗交叉研究，40名健康志愿者（年龄20 - 33岁）接受单次36毫克剂量的希美加群，以三种不同方式给药：I. 整片吞服；II. 碾碎，与苹果酱混合后服用；III. 溶于水后经鼻胃管给药。
测定了希美加群及其中间体和活性形式美拉加群的血浆浓度。希美加群吸收迅速，三种不同给药方式后美拉加群的生物利用度相似，符合生物等效性标准。美拉加群的血浆浓度 - 时间曲线下平均面积（AUC）为1.6微摩尔·小时/升（治疗II/I的比值为1.01，治疗III/I的比值为0.97），平均峰浓度（C(max)）为0.3微摩尔/升（治疗II/I的比值为1.04，治疗III/I的比值为1.02），所有治疗的平均半衰期（t(1/2)）为2.8小时。整片给药时达到C(max)的时间（t(max)）为2.2小时，碾碎或溶解片剂时（1.7 - 1.8小时）由于吸收更快，时间提前约0.5小时。根据报告的不良事件发生率和类型判断，研究药物耐受性良好。
本研究表明，无论希美加群是碾碎与苹果酱混合口服还是溶于水经鼻胃管给药，美拉加群的药代动力学（AUC和C(max)）均无显著改变。
