title: Preclinical disposition and pharmacokinetics-pharmacodynamic modeling of biomarker response and tumour growth inhibition in xenograft mouse models of G-573, a MEK inhibitor.
abstract: 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 (~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 IC(50) value for pERK inhibition in HCT116 tumours by G-573 was estimated to be 0.406  µM. The IC(50) values for tumour growth inhibition in HCT116 and H2122 were estimated to be 3.43 and 2.56 µM, respectively. ED(50) 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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, South San Francisco, CA 94080, USA. choo.edna@gene.com
authors.forename: Edna F
authors.initials: EF
authors.lastname: Choo
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Chan
authors.forename: Klaus
authors.initials: K
authors.lastname: Hoeflich
authors.forename: Christine
authors.initials: C
authors.lastname: Orr
authors.forename: Kirk
authors.initials: K
authors.lastname: Robarge
authors.forename: Xiaoye
authors.initials: X
authors.lastname: Yang
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
authors.forename: Jason
authors.initials: J
authors.lastname: Boggs
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D054316:Biomarkers, Pharmacological; D004285:Dogs; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D005663:Furans / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D045325:HCT116 Cells; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D023041:Xenograft Model Antitumor Assays
chemical_list: C555359:7-fluoro-3-(2-fluoro-4-iodophenylamino)-N-(2-hydroxypropoxy)furo(3,2-c)pyridine-2-carboxamide; D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D005663:Furans; D011725:Pyridines; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases