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

Abstract

1. 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.

2. 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.

3. 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 (~2–9 h).

4. 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 μM. The IC₅₀ values for tumour growth inhibition in HCT116 and H2122 were estimated to be 3.43 and 2.56 μM, respectively. ED₅₀ estimates in HCT116 and H2122 mouse xenograft models were estimated to be ~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.

Keywords::

• Oncology
• indirect response model
• PK-PD

Acknowledgements

The authors thank Argenta Discovery and our Genentech colleagues in the Translational Oncology, DMPK and the in vivo studies group for their contributions in generating data for this study.

Declaration of interest

The authors report no declarations of interest