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

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. Overall, GNE-A exhibited favourable preclinical properties and projected human dose estimates.

Keywords::

• MET
• absorption
• distribution
• pharmacokinetics
• pharmacokinetic–pharmacodynamic
• allometry
• human prediction
• disposition

Acknowledgements

The authors thank the Medicinal Chemistry Groups, especially Drs John Gaudino and Dan Sutherlin, Translational Oncology Group, In Vivo Studies Group, Pharmaceutics Group and DMPK Groups at Array BioPharma, Inc. and Genentech, Inc. for their contribution to the generation of the data in this manuscript.

Declaration of interest

The authors report no declarations of interest. The authors are employees of Array BioPharma, Inc. and Genentech, Inc. and are alone responsible for the content and writing of this manuscript.