Preclinical disposition and pharmacokinetics-pharmacodynamic modeling of biomarker response and tumour growth inhibition in xenograft mouse models of G-573, a MEK inhibitor

被引:17
作者
Choo, Edna F. [1 ]
Belvin, Marcia [2 ]
Chan, Jocelyn [2 ]
Hoeflich, Klaus [2 ]
Orr, Christine [2 ]
Robarge, Kirk [3 ]
Yang, Xiaoye
Zak, Mark [3 ]
Boggs, Jason
机构
[1] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA
[2] Dept Canc Signaling & Translat Oncol, San Francisco, CA USA
[3] Genentech Inc, Dept Chem, San Francisco, CA 94080 USA
关键词
Oncology; indirect response model; PK-PD; PROTEIN-KINASE CASCADE; PHASE-I; EFFICACY;
D O I
10.3109/00498254.2010.514365
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) pathway is a key signalling pathway that regulates cell proliferation. G-573 is an allosteric inhibitor of MEK that is both potent and selective. The objectives of these studies were to characterize the disposition of G-573 in preclinical species and to determine the relationship of G-573 plasma concentrations to pERK (phosphorylated ERK) and to tumour growth inhibition in HCT116 and H2122 mouse xenograft models. The clearance of G-573 was low in mouse (7.7 ml/min/kg), rat (2.24 ml/min/kg), dog (10 ml/min/kg), and cynomolgus monkey (0.754 ml/min/kg) while volumes of distribution (0.114-1.77 l/kg) was low to moderate, resulting in moderate half-lives across species (similar to 2-9 h). Indirect response models were used to characterize the relationship between plasma concentration of G-573 to both pERK inhibition and tumour growth inhibition. The IC50 value for pERK inhibition in HCT116 tumours by G-573 was estimated to be 0.406 mu M. The IC50 values for tumour growth inhibition in HCT116 and H2122 were estimated to be 3.43 and 2.56 mu M, respectively. ED50 estimates in HCT116 and H2122 mouse xenograft models were estimated to be similar to 4.6 and 1.9 mg/kg/day, respectively. The information from these studies provides useful information when characterizing candidates for potential further clinical testing.
引用
收藏
页码:751 / 762
页数:12
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