Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
J Hematol Oncol. 2013 Jul 8;6:48. doi: 10.1186/1756-8722-6-48.
Ridaforolimus (AP23573, MK-8669 or deforolimus) is an inhibitor of mammalian target of rapamycin (mTOR), an important regulator in the cell survival pathway. This open-label, single center phase I study aimed to investigate the pharmacokinetic (PK) and safety profiles of ridaforolimus in Chinese patients with treatment-refractory advanced or relapsed solid tumors. The PK data generated from these Chinese patients were further compared with those previously reported in Caucasian and Japanese patient populations.
The patients were given an oral dose of 40 mg of ridaforolimus on Day 1 of the study. On Day 8, patients were initiated on a treatment regimen that comprised a once daily dose of 40 mg of ridaforolimus for five consecutive days, followed by a 2-day off-drug interval. Patients repeated this regimen until disease progression or intolerance. Blood samples were collected at specific times pre- and post-treatment to establish the PK profile of ridaforolimus in all patients.
Fifteen patients were given at least one dose of 40 mg of ridaforolimus. The median absorption lag-time was 2 hours, the median Tmax was 4 hours and the mean elimination half-life was 53 hours. The accumulation ratio for AUC(0-24hr) was 1.3 on day 19 (steady state)/day 1 (after a single dose). The most common drug-related adverse events (AEs) that occurred in ≥40% of patients were stomatitis, proteinuria, leukopenia, hyperglycemia, and pyrexia. Grade 3/4 drug-related AEs were anemia, stomatitis, fatigue, thrombocytopenia, constipation, gamma glutamyltransferase increase, and proteinuria. All 11 evaluable patients achieved stable disease.
Oral ridaforolimus at a daily dose of 40 mg were generally well tolerated in Chinese patients with advanced or refractory solid tumors. Adverse events and PK profiles of ridaforolimus in this study were similar to those from Caucasian and Japanese patients reported previously.
瑞达福罗默（AP23573、MK-8669 或德福罗默）是一种哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，mTOR 是细胞存活途径中的重要调节剂。这项开放标签、单中心 I 期研究旨在研究瑞达福罗默在治疗耐药性晚期或复发性实体瘤的中国患者中的药代动力学（PK）和安全性特征。从这些中国患者中获得的 PK 数据还与以前在白人和日本患者人群中报告的数据进行了比较。
患者在研究的第 1 天接受 40 毫克瑞达福罗默的口服剂量。第 8 天，患者开始接受治疗方案，方案包括连续 5 天每天一次给予 40 毫克瑞达福罗默，然后停药 2 天。患者重复此方案，直到疾病进展或不耐受。在治疗前后的特定时间采集血样，以建立所有患者的瑞达福罗默 PK 特征。
15 名患者至少接受了一次 40 毫克瑞达福罗默的治疗。中位吸收滞后时间为 2 小时，中位 Tmax 为 4 小时，平均消除半衰期为 53 小时。AUC（0-24hr）的蓄积比在第 19 天（稳态）/第 1 天（单次剂量后）为 1.3。发生在≥40%患者中的最常见的药物相关不良事件（AE）是口炎、蛋白尿、白细胞减少症、高血糖和发热。3/4 级药物相关 AE 是贫血、口炎、疲劳、血小板减少症、便秘、γ-谷氨酰转移酶升高和蛋白尿。11 名可评估的患者均达到稳定的疾病。
在中国晚期或难治性实体瘤患者中，每天口服 40 毫克瑞达福罗默通常耐受良好。该研究中瑞达福罗默的不良反应和 PK 特征与以前报告的白人和日本患者相似。
