Concomitant oral and intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours
Concomitant oral and intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours
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DOI：
10.1111/bcp.12373
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发表时间：
2014-09-01
影响因子：
3.4
通讯作者：
Ouellet, Daniele
中科院分区：
文献类型：
--
作者：
Leonowens, Cathrine;Pendry, Carolyn;Ouellet, Daniele
目的：在4名实体肿瘤患者中进行这项1期、单中心、开放标签研究的目的是确定口服2毫克曲美替尼的绝对生物利用度。曲美替尼是一种口服生物利用度、可逆性和选择性的MEK1和MEK2激活和激酶活性的变构抑制剂。小剂量曲美替尼与无标记的2 mg口服片剂同时给予，用于静脉注射。结果曲美替尼2 mg片剂的绝对生物利用度(90%可信区间)为72.3%(50.0%，104.6%)。口服后的中位t(Max)为1.5h，几何平均终末半衰期为11d。静脉注射后的几何平均间隙和分布体积。给药浓度分别为3.21h(-1)和976h(-1)，终末消除半衰期分别为11d。结论曲美替尼的绝对生物利用度为中高，首过代谢低。
AIMSThe aim of this phase 1, single centre, open label study in four patients with solid tumours was to determine the absolute bioavailability of a 2 mg oral dose of trametinib. Trametinib is an orally bioavailable, reversible and selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity.METHODSA microtracer study approach, in which a 5 g radiolabelled i.v. microdose of trametinib was given concomitantly with an unlabelled 2 mg oral tablet formulation, was used to recover i.v. and oral pharmacokinetic parameters, simultaneously.RESULTSThe least-squares mean (90% confidence interval) absolute bioavailability of trametinib (2 mg tablet) was 72.3% (50.0%, 104.6%). Median t(max) after oral administration was 1.5 h and the geometric mean terminal half-life was 11 days. The geometric mean clearance and volume of distribution after i.v. administration were 3.21 l h(-1) and 976 l, respectively, resulting in a terminal elimination half-life of 11 days.CONCLUSIONSTrametinib absolute bioavailability was moderate to high, whereas first pass metabolism was low.