Huang Liyue, Be Xuhai, Berry Loren, Moore Earl, Janosky Brett, Wells Mary, Pan Wei-Jian, Zhao Zhiyang, Lin Min-Hwa Jasmine
Pharmacokinetics and Drug Metabolism, Amgen Inc., Cambridge, MA 02142, USA.
Xenobiotica. 2011 May;41(5):400-8. doi: 10.3109/00498254.2010.548534. Epub 2011 Feb 4.
AMG 900 is a small molecule being developed as an orally administered, highly potent, and selective pan-aurora kinase inhibitor. The aim of the investigations was to characterize in vitro and in vivo pharmacokinetic (PK) properties of AMG 900 in preclinical species. AMG 900 was rapidly metabolized in liver microsomes and highly bound to plasma proteins in the species tested. It was a weak Pgp substrate with good passive permeability. AMG 900 exhibited a low-to-moderate clearance and a small volume of distribution. Its terminal elimination half-life ranged from 0.6 to 2.4 h. AMG 900 was well-absorbed in fasted animals with an oral bioavailability of 31% to 107%. Food intake had an effect on rate (rats) or extent (dogs) of AMG 900 oral absorption. The clearance and volume of distribution at steady state in humans were predicted to be 27.3 mL/h/kg and 93.9 mL/kg, respectively. AMG 900 exhibited acceptable PK properties in preclinical species and was predicted to have low clearance in humans. AMG 900 is currently in Phase I clinical testing as a treatment for solid tumours. Preliminary human PK results appear to be consistent with the predictions.
AMG 900是一种正在研发的小分子化合物，作为口服给药的高效、选择性泛极光激酶抑制剂。研究目的是在临床前物种中表征AMG 900的体外和体内药代动力学（PK）特性。AMG 900在肝微粒体中迅速代谢，在所测试的物种中与血浆蛋白高度结合。它是一种弱P-糖蛋白底物，具有良好的被动通透性。AMG 900的清除率低至中等，分布容积小。其终末消除半衰期为0.6至2.4小时。AMG 900在禁食动物中吸收良好，口服生物利用度为31%至107%。食物摄入对AMG 900的口服吸收速率（大鼠）或程度（犬）有影响。预计人体稳态时的清除率和分布容积分别为27.3 mL/h/kg和93.9 mL/kg。AMG 900在临床前物种中表现出可接受的PK特性，预计在人体中的清除率较低。AMG 900目前正处于治疗实体瘤的I期临床试验阶段。初步的人体PK结果似乎与预测一致。
