作者
Nicola Colclough, Kan Chen, Peter Johnström, Nicole Strittmatter, Yumei Yan, Gail L Wrigley, Magnus Schou, Richard Goodwin, Katarina Varnäs, Sally J Adua, Minghui Zhao, Don X Nguyen, Gareth Maglennon, Peter Barton, James Atkinson, Lin Zhang, Annika Janefeldt, Joanne Wilson, Aaron Smith, Akihiro Takano, Ryosuke Arakawa, Mikhail Kondrashov, Jonas Malmquist, Evgeny Revunov, Ana Vazquez-Romero, Mohammad Mahdi Moein, Albert D Windhorst, Natasha A Karp, M Raymond V Finlay, Richard A Ward, James WT Yates, Paul D Smith, Lars Farde, Zack Cheng, Darren AE Cross
发表日期
2021/1/1
期刊
Clinical Cancer Research
卷号
27
期号
1
页码范围
189-201
出版商
American Association for Cancer Research
简介
Purpose
Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood–brain barrier (BBB) permeability is considered desirable for increasing clinical efficacy.
Experimental Design
We examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple in vitro and in vivo BBB preclinical models.
Results
In vitro osimertinib was the weakest substrate for human BBB efflux transporters (efflux ratio 3.2). In vivo rat free brain to free plasma ratios (Kpuu) show osimertinib has the most BBB penetrance (0.21), compared with the other TKIs (Kpuu ≤ 0.12). PET imaging in Cynomolgus macaques demonstrated osimertinib was the only TKI among those tested to achieve significant brain penetrance (Cmax %ID 1.5, brain …
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N Colclough, K Chen, P Johnström, N Strittmatter… - Clinical Cancer Research, 2021