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

Abstract

1. 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.

2. 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.

3. 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 KC₅₀ (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 IC₅₀ for pERK inhibition in Colo205 tumors by G-F was estimated to be 29.2 μM.

4. 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.

Keywords::

• BRAF
• pharmacokinetics
• PK-PD modelling
• mouse xenograft

Acknowledgements

The authors thank Array BioPharma and Genentech colleagues in the Translational Oncology, DMPK and In Vivo Studies Group for their contributions in generating data for this study.

Declaration of interest

The authors declare no conflict of interest.