title: Preclinical absorption, distribution, metabolism, excretion, and pharmacokinetic-pharmacodynamic modelling of N-(4-(3-((3S,4R)-1-ethyl-3-fluoropiperidine-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, a novel MET kinase inhibitor.
abstract: GNE-A (AR00451896; N-(4-(3-((3S,4R)-1-ethyl-3-fluoropiperidine-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide) is a potent, selective MET kinase inhibitor being developed as a potential drug for the treatment of human cancers. Plasma clearance was low in mice and dogs (15.8 and 2.44 mL/min/kg, respectively) and moderate in rats and monkeys (36.6 and 13.9 mL/min/kg, respectively). The volume of distribution ranged from 2.1 to 9.0 L/kg. The mean terminal elimination half-life ranged from 1.67 h in rats to 16.3 h in dogs. Oral bioavailability in rats, mice, monkeys, and dogs were 11.2%, 88.0%, 72.4%, and 55.8%, respectively. Allometric scaling predicted a clearance of 1.3-7.4 mL/min/kg and a volume of distribution of 4.8-11 L/kg in human. Plasma protein binding was high (96.7-99.0% bound). Blood-to-plasma concentration ratios (0.78-1.46) indicated that GNE-A did not preferentially distribute into red blood cells. Transporter studies in MDCKI-MDR1 and MDCKII-Bcrp1 cells suggested that GNE-A is likely a substrate for MDR1 and BCRP. Pharmacokinetic-pharmacodynamic modelling of tumour growth inhibition in MET-amplified EBC-1 human non-small cell lung carcinoma tumour xenograft mice projected oral doses of 5.6 and 13 mg/kg/day for 50% and 90% tumour growth inhibition, respectively. Overall, GNE-A exhibited favourable preclinical properties and projected human dose estimates.
authors.affiliation: Genentech, Inc., Drug Metabolism and Pharmacokinetics, South San Francisco, CA 94080, USA. liederer.bianca@gene.com
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.forename: Leonid M
authors.initials: LM
authors.lastname: Berezhkovskiy
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Dean
authors.forename: Vikki
authors.initials: V
authors.lastname: Dinkel
authors.forename: Jing
authors.initials: J
authors.lastname: Peng
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Emile G
authors.initials: EG
authors.lastname: Plise
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
mesh_terms: D000042:Absorption; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011724:Pyridazines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; C558221:N-(4-(3-(1-ethyl-3-fluoropiperidine-4-ylamino)-1H-pyrazolo(3,4-b)pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; D019859:Proto-Oncogene Proteins c-met