Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice.
Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice.
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DOI：
10.1007/s00280-010-1323-z
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发表时间：
2011-02
影响因子：
3
通讯作者：
Gustafson, Daniel L.
中科院分区：
文献类型：
--
作者：
Denton, Cathrine L.;Gustafson, Daniel L.
AZD 6244（ARRY-142886）（AstraZeneca，Macclesfield，UK）是一种新型小分子MEK 1/2抑制剂，目前正在II期试验中进行测试。随着最近发表的临床研究的人体药代动力学数据，我们现在知道了AZD 6244在人体中可达到的暴露水平和范围。本研究旨在描述AZD 6244在小鼠中的药代动力学特征，以设计概括人体暴露水平的临床前研究。雄性无胸腺裸鼠皮下接种A375人黑色素瘤细胞。一旦肿瘤达到400-700 mm 3，通过经口灌胃给予小鼠5或10 mg/kg AZD 6244的单次剂量。此外，对小鼠亚组每日给药一次，持续1周（10 mg/kg）。在末次给药后的不同时间点处死小鼠并收集血浆和组织。通过LC/MS/MS分析样品的AZD 6244浓度。此外，在末次给药后的不同时间点分析药效学终点，如肿瘤增殖和ERK磷酸化。单次给药或稳态给药后，在临床等效暴露量下，AZD 6244可有效抑制ERK磷酸化并抑制增殖。此外，我们描述了AZD 6244的药代动力学和药效学与靶向和药理学反应之间的滞后关系。本文提供的信息将推动临床前研究的合理设计，这些研究不仅与临床环境相关，而且为了解AZD 6244治疗的生物学反应铺平了道路。
AZD6244 (ARRY-142886) (AstraZeneca, Macclesfield, UK) is a novel small molecule MEK1/2 inhibitor that is currently being tested in Phase II trials. With the recent publication of human pharmacokinetic data from clinical studies, we now know the achievable levels and range of AZD6244 exposure in humans. This study aimed to describe the pharmacokinetic profile of AZD6244 in mice in order to design preclinical studies that recapitulate exposure levels in humans. Male athymic, nude mice received subcutaneous inoculation of A375 human melanoma cells. Once tumors reached 400–700 mm3, mice were given a single dose of either 5 or 10 mg/kg AZD6244 via oral gavage. Additionally, a subset of mice was dosed once daily for 1 week (10 mg/kg). Mice were killed and plasma and tissues were collected at various time points after the last dose. Samples were analyzed by LC/MS/MS for AZD6244 concentration. Additionally, pharmacodynamic endpoints such as tumor proliferation and ERK phosphorylation were analyzed at various time points after the last dose. After either a single dose or at steady state, at clinically equivalent exposures, AZD6244 effectively inhibits ERK phosphorylation and suppresses proliferation. Furthermore, we describe a hysteretic relationship between the pharmacokinetics and the pharmacodynamics of AZD6244 and both target and pharmacologic responses. The information presented herein will drive the rational design of pre-clinical studies that are not only relevant to the clinical setting, but also pave the way to understand the biological response to AZD6244 treatment.
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