Johansson Linda C, Frison Lars, Logren Ulrika, Fager Gunnar, Gustafsson David, Eriksson Ulf G
AstraZeneca R&D Mölndal, Mölndal, Sweden.
Clin Pharmacokinet. 2003;42(4):381-92. doi: 10.2165/00003088-200342040-00006.
To investigate the influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran.
This was an open-label, randomised, 3 x 3 crossover study with 4 study days, separated by washout periods of 7 days.
Subjects comprised 6 healthy young men (aged 20-27 years) and 12 healthy older men and women (aged 56-70 years).
All subjects received a 2mg intravenous infusion of melagatran over 10 minutes followed, in randomised sequence, by a 20 mg immediate-release tablet of ximelagatran with breakfast, a 20 mg immediate-release tablet of ximelagatran while fasting, and a 7.5 mg subcutaneous injection of ximelagatran. The primary variables were the plasma concentration of melagatran, the active form of ximelagatran, and the activated partial thromboplastin time (APTT), an ex vivo coagulation time measurement used to demonstrate inhibition of thrombin.
After oral and subcutaneous administration, ximelagatran was rapidly absorbed and biotransformed to melagatran, its active form and the dominant compound in plasma. The metabolite pattern in plasma and urine was similar in young and older subjects after both oral and subcutaneous administration of ximelagatran clearance of melagatran was correlated with renal function, resulting in about 40% (after intravenous melagatran) to 60% (after oral and subcutaneous ximelagatran) higher melagatran exposure in the older than in the young subjects. Renal clearance of melagatran, was 7.7 L/h and 4.9 L/h in the younger and older subjects, respectively. The interindividual variability inn the area under the melagatran plasma concentration-time curve was low following all regimens (coefficient variation 12-25%). The mean bioavailability of melagatran in young and older subjects was approximately 18 and 12% , respectively, following oral administration of ximalagratan, and 38 and 45%, respectively, following subcutaneous administration of ximelagatran. The bioavailability of melagatran following oral administration of ximelagatran was unaffected by whether subjects were fed or fasting, although the plasma concentration of melagatran peaked about 1 hour later under fed than fasting conditions, due to gastric emptying of the immediate-release tablet formulation used. The APTT as prolonged with increasing melagatran plasma concentration-effect relationship was independent of age.
There were no age-dependent differences in the absorption and biotransformation of ximelagatran, and the observed differences in exposure to melagatran can be explained by differences in renal function between the young and older subjects.
研究年龄对希美加群药代动力学和药效学的影响。
这是一项开放标签、随机、3×3交叉研究，为期4个研究日，中间间隔7天的洗脱期。
受试者包括6名健康年轻男性（年龄20 - 27岁）和12名健康老年男性及女性（年龄56 - 70岁）。
所有受试者先在10分钟内静脉输注2mg美拉加群，随后按随机顺序，分别在早餐时服用20mg希美加群速释片、空腹时服用20mg希美加群速释片以及皮下注射7.5mg希美加群。主要变量为美拉加群的血浆浓度（希美加群的活性形式）以及活化部分凝血活酶时间（APTT，一种用于证明凝血酶抑制作用的体外凝血时间测量指标）。
口服和皮下给药后，希美加群迅速吸收并生物转化为美拉加群，其活性形式以及血浆中的主要化合物。口服和皮下给予希美加群后，年轻和老年受试者血浆及尿液中的代谢物模式相似。美拉加群的清除率与肾功能相关，导致老年受试者中美拉加群的暴露量比年轻受试者高约40%（静脉注射美拉加群后）至60%（口服和皮下注射希美加群后）。年轻和老年受试者中美拉加群的肾清除率分别为7.7L/h和4.9L/h。在所有给药方案下，美拉加群血浆浓度 - 时间曲线下面积的个体间变异性较低（变异系数12 - 25%）。口服希美加群后，年轻和老年受试者中美拉加群的平均生物利用度分别约为18%和12%，皮下注射希美加群后分别为38%和45%。口服希美加群后美拉加群的生物利用度不受受试者进食或空腹状态的影响，尽管由于所用速释片剂型的胃排空，进食状态下美拉加群的血浆浓度峰值比空腹状态下约晚1小时出现。APTT随美拉加群血浆浓度升高而延长，效应关系与年龄无关。
希美加群的吸收和生物转化不存在年龄依赖性差异，观察到的美拉加群暴露量差异可由年轻和老年受试者肾功能的差异来解释。
