SNS-032(原BMS-387032)是一种周期蛋白依赖性激酶2、7和9的有效抑制剂，用于转移性难治性实体瘤患者的单次口服和每周输注。
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Heath EI, Bible K, Martell RE, Adelman DC, Lorusso PM
SNS-032(原BMS-387032)是一种周期蛋白依赖性激酶2、7和9的有效抑制剂，用于转移性难治性实体瘤患者的单次口服和每周输注。
投资新药。2008 Feb;26(1):59-65。Epub 2007 10月16日。
- PubMed ID
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17938863 (PubMed视图]
- 摘要
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目的:ssn -032(原BMS-387032)是一种有效的选择性周期蛋白依赖性激酶(CDK) 2,7和9抑制剂。该研究的主要目的是确定SNS-032的最大耐受剂量(MTD)、最大给药剂量(MAD)、剂量限制毒性(DLT)以及每周1小时输注时的推荐2期剂量。次要目标是评估ssn -032的安全性和耐受性，并评估其作为口服溶液的生物利用度。方法:转移性实体瘤或难治性淋巴瘤患者接受起始剂量4 mg/m2静脉给药1小时，周期定义为每21天3周剂量的ssn -032。在剂量递增模式中使用了三个患者队列。进行了药代动力学研究。对于13和16 mg/m2剂量组，周期2的第一剂量作为口服溶液给予，以评估药物在人体内的口服生物利用度。结果:共纳入21例患者。20名接受治疗的患者总共接受了39个周期的治疗。发生率高于20%的最常见治疗相关不良事件为疲劳(25%)和恶心(20%)。 Following intravenous administration, plasma concentrations declined in a biphasic manner, resulting in mean terminal half-lives between 5 and 10 hours. The mean Cmax and AUC0-inf increased nearly linearly with dose, ranging from 0.067 to 0.287 microg/ml and 0.103 to 0.553 microg h/ml, respectively. The CL and Vss remained unchanged with increasing dose levels, averaging 38 l/h/m2 and 212 l/m2, respectively. Average oral bioavailability was 19% (range: 4-33%). Three (15%) patients experienced a best response of stable disease. Study enrollment was terminated during dose-escalation due to a change in the development strategy for the study drug. CONCLUSIONS: SNS-032 administered as a weekly 1-h infusion was well tolerated, although study enrollment was terminated during dose-escalation and the MTD of SNS-032 administered intravenously on days 1, 8, and 15 of each treatment cycle was not reached. Tumor progression or stable disease was determined to be the best response in all evaluable patients. At the dose levels tested, the oral bioavailability of SNS-032 ranged from 4-33%. The data suggest that oral administration of SNS-032 may be feasible, though the tolerability and bioavailability of the oral formulation would have to be formally assessed.
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