Williams Daphne D, Peng Bin, Bailey Christine K, Wire Mary B, Deng Yanli, Park Jung Wook, Collins David A, Kapsi Shiva G, Jenkins Julian M
GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Clin Ther. 2009 Apr;31(4):764-76. doi: 10.1016/j.clinthera.2009.04.010.
Eltrombopag is the first orally self-administered, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura.
The aim of these studies was to assess the effect of food and antacids on the pharmacokinetic and safety profiles of eltrombopag.
Two independent, single-dose, open-label, randomized-sequence, crossover studies of oral eltrombopag were conducted in healthy adult volunteers. The first study (study A) compared eltrombopag 50 mg (tablets or capsules) administered in the fasted state or tablets with a high-fat, high-calcium breakfast. The second study (study B) investigated eltrombopag tablets (75 mg) administered in the fasted state; immediately after a low-fat, low-calcium meal or a high-fat, low-calcium meal; 1 hour before a high-fat, low-calcium meal; or with an antacid containing aluminum hydroxide and magnesium carbonate. Vital signs were recorded and electrocardiogram and clinical laboratory tests were performed at screening, within 24 hours before and within 48 hours after each dose of study medication. Symptom assessment was performed and adverse events (AEs) were assessed previous to study drug administration through follow-up in terms of severity and relationship to study medication.
In study A, 18 male subjects (mean age, 23.0 years; weight, 70.3 kg; white race, 94.4%) who received a high-fat, high-calcium breakfast had reduced bioavailability of eltrombopag in terms of AUC(0-infinity)) by 59% (geometric mean ratio [GMR], 0.41; 90% CI, 0.36-0.46) and C(max) by 65% (GMR, 0.35; 90% CI, 0.30-0.41) compared with subjects in a fasted state. In study B, the bioavailability in 26 subjects (14 male, 12 female; mean age, 35.6 years; weight, 76.0 kg; white race, 65.4%) was not significantly changed when administered with food that was low in calcium, despite the fat content (GMRs ranged from 0.87-1.03 for AUC(0-infinity) and 0.85-1.01 for C(max) across the 3 studied meals). Mean plasma AUC(0-infinity)) and C(max) values decreased by approximately 70% (GMR, 0.30; 90% CI, 0.24-0.36 for AUC(0-infinity)) and 0.24-0.38 for C(max)) when administered with a metal cation-containing antacid. No serious AEs were reported and all AEs were rated as mild to moderate in intensity. The most frequently reported AE was headache (study A, 6.3%; study B, 12.0%-29.2%).
Concomitant administration of eltrombopag with high-calcium food or an antacid containing aluminum and magnesium was associated with significantly reduced systemic exposure, whereas low-calcium meals were not. A single dose of eltrombopag was generally well tolerated in these healthy volunteers.
艾曲泊帕是首个口服自给药的小分子非肽类血小板生成素受体激动剂，用于治疗慢性特发性血小板减少性紫癜。
这些研究旨在评估食物和抗酸剂对艾曲泊帕药代动力学及安全性的影响。
在健康成年志愿者中开展了两项独立的口服艾曲泊帕单剂量、开放标签、随机序列、交叉研究。第一项研究（研究A）比较了在禁食状态下服用的50毫克艾曲泊帕（片剂或胶囊）与搭配高脂高钙早餐的片剂。第二项研究（研究B）调查了在禁食状态下；低脂低钙餐后或高脂低钙餐后立即；高脂低钙餐前1小时；或与含氢氧化铝和碳酸镁的抗酸剂一起服用的75毫克艾曲泊帕片剂。记录生命体征，并在筛选时、每次服用研究药物前24小时内及服用后48小时内进行心电图和临床实验室检查。在给药前进行症状评估，并通过随访评估不良事件（AE）的严重程度及其与研究药物的关系。
在研究A中，18名接受高脂高钙早餐的男性受试者（平均年龄23.0岁；体重70.3千克；白种人占94.4%），与禁食状态下的受试者相比，艾曲泊帕的生物利用度在AUC(0-∞)方面降低了59%（几何平均比值[GMR]，0.41；90%置信区间，0.36-0.46），C(max)降低了65%（GMR，0.35；90%置信区间，0.30-0.41）。在研究B中，26名受试者（14名男性，12名女性；平均年龄35.6岁；体重76.0千克；白种人占65.4%）在与低钙食物一起服用时，尽管食物脂肪含量不同，生物利用度没有显著变化（在3种研究餐中，AUC(0-∞)的GMR范围为0.87-1.03，C(max)的GMR范围为0.85-1.01）。与含金属阳离子的抗酸剂一起服用时，平均血浆AUC(0-∞)和C(max)值分别下降了约70%（AUC(0-∞)的GMR，0.30；90%置信区间，0.24-0.36；C(max)的GMR，0.24-0.38）。未报告严重不良事件，所有不良事件的强度均评为轻度至中度。最常报告的不良事件是头痛（研究A，6.3%；研究B，12.0%-29.2%）。
艾曲泊帕与高钙食物或含铝镁的抗酸剂同时服用会导致全身暴露显著降低，而低钙餐则不会。在这些健康志愿者中，单剂量艾曲泊帕通常耐受性良好。
