Preclinical assessment of novel BRAF inhibitors: integrating pharmacokinetic-pharmacodynamic modelling in the drug discovery process.

The objective of these studies were to determine the preclinical disposition of the two BRAF inhibitors, G-F and G-C, followed by pharmacokinetic (PK)-pharmacodynamic (PD) modelling to characterize the concentration-efficacy relationship of these compounds in the Colo205 mouse xenograft model. With G-F, the relationship of pERK inhibition to concentration was also characterized. Compounds G-F and G-C were administered to mice, rats and dogs and the pharmacokinetics of G-F and G-C was determined. In addition, using indirect response models the concentration-efficacy relationship was described. The clearance of G-F was low; 0.625 and 4.65 mL/min/kg in rat and dog respectively. Similarly, the clearance of G-C was low in rat and dog, 0.490 and 4.43 mL/min/kg, respectively. Both compounds displayed low volumes of distribution (0.140-0.267 L/kg), resulting in moderate half-lives across species (~2.5 to 4 h). Bioavailability was formulation dependent and decreased with increasing dose. Using the indirect response models, the KC(50) (50% K(max); maximal response) value for tumor growth inhibition for G-F and G-C were 84.5 and 19.2 µM, respectively. The IC(50) for pERK inhibition in Colo205 tumors by G-F was estimated to be 29.2 µM. High exposures of G-F and G-C were required for efficacy. Despite good PK properties of low CL and moderate half-life, limitations in obtaining exposures adequate for safety testing in rat and dog resulted in development challenges.

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.

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.