Small David S, Wrishko Rebecca E, Ernest C Steven, Ni Lan, Winters Kenneth J, Farid Nagy A, Li Ying G, Salazar Daniel E, Payne Christopher D
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
Drugs Aging. 2009;26(9):781-90. doi: 10.2165/11315780-000000000-00000.
A substantial portion of patients at risk for acute coronary syndrome (ACS) are >65 years old. Prasugrel is a novel antiplatelet agent approved for the treatment of ACS patients undergoing percutaneous coronary intervention, and will be used in this population.
This study assessed the effect of age >or=65 years on the pharmacokinetics (PK) and pharmacodynamics (PD) of the active metabolite (R-138727) of prasugrel in healthy subjects taking aspirin (acetylsalicylic acid).
This was an open-label, single-sequence trial conducted in a single clinical research centre in the UK. A total of 17 subjects aged 65-80 years and 15 subjects aged 20-39 years received a prasugrel 5-mg once-daily maintenance dose for 10 days followed by 10-mg once daily maintenance doses for 10 days. All subjects also received aspirin 75 mg daily. Serial blood samples were collected pre-dose and at various times post-dose for measurement of the active metabolite of prasugrel in plasma on days 10 and 20, following the last 5- and 10-mg prasugrel dose, respectively. PK parameters of the active metabolite of prasugrel included area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUC(last)), maximum plasma concentration (C(max)) and time to C(max) (t(max)). Maximal platelet aggregation (MPA), assessed by light transmission aggregometry using adenosine diphosphate (ADP) 20 micromol/L, was assessed at baseline and on day 10 (5-mg maintenance dose) and day 20 (10-mg maintenance dose). Bleeding times (BTs) were determined on days -5, 1, 10, 11, 20 and 21 using a modified Ivy technique.
AUC(last) did not differ significantly between age groups. The steady-state trough MPA to ADP 20 micromol/L during 10-mg maintenance dosing was 30.6% and 26.6% in elderly and young subjects, respectively. Mean MPA was consistently higher in elderly subjects compared with young subjects; however, differences were generally less than ten percentage points. BTs did not differ between the two populations during 5-mg maintenance dosing; however, during 10-mg maintenance dosing, BTs were up to 67% longer in young compared with elderly subjects. A higher frequency of minor bleeding during 10-mg maintenance dosing was observed in elderly subjects compared with young subjects.
These data indicate that prasugrel PK and MPA were similar in healthy subjects regardless of age. Compared with younger subjects, elderly subjects had shorter BTs but a greater frequency of mild bleeding-related adverse events.
很大一部分有急性冠状动脉综合征（ACS）风险的患者年龄大于65岁。普拉格雷是一种新型抗血小板药物，已被批准用于治疗接受经皮冠状动脉介入治疗的ACS患者，并将用于该人群。
本研究评估年龄≥65岁对服用阿司匹林（乙酰水杨酸）的健康受试者中普拉格雷活性代谢物（R - 138727）的药代动力学（PK）和药效学（PD）的影响。
这是一项在英国单个临床研究中心进行的开放标签、单序列试验。共有17名年龄在65 - 80岁的受试者和15名年龄在20 - 39岁的受试者接受每日一次5毫克的普拉格雷维持剂量，持续10天，随后每日一次10毫克的维持剂量，持续10天。所有受试者还每日服用75毫克阿司匹林。在第10天和第20天，分别在最后一次服用5毫克和10毫克普拉格雷剂量后，于给药前和给药后的不同时间点采集系列血样，以测量血浆中普拉格雷的活性代谢物。普拉格雷活性代谢物的PK参数包括从零时间到最后可定量浓度时间的血浆浓度 - 时间曲线下面积（AUC（last））、最大血浆浓度（C（max））和达到C（max）的时间（t（max））。使用20微摩尔/升二磷酸腺苷（ADP）通过光透射聚集法评估的最大血小板聚集（MPA）在基线以及第10天（5毫克维持剂量）和第20天（10毫克维持剂量）进行评估。使用改良的Ivy技术在第 - 5、1、10、11、20和21天测定出血时间（BT）。
年龄组之间的AUC（last）无显著差异。在10毫克维持给药期间，老年和年轻受试者中对20微摩尔/升ADP的稳态谷MPA分别为30.6%和26.6%。与年轻受试者相比，老年受试者的平均MPA始终较高；然而，差异通常小于10个百分点。在5毫克维持给药期间，两个人群的BT无差异；然而，在10毫克维持给药期间，年轻受试者的BT比老年受试者长多达67%。与年轻受试者相比，在10毫克维持给药期间，老年受试者中轻微出血的发生率更高。
这些数据表明，无论年龄大小，健康受试者中普拉格雷的PK和MPA相似。与年轻受试者相比，老年受试者的BT较短，但轻度出血相关不良事件的发生率较高。
