title: Preclinical assessment of novel BRAF inhibitors: integrating pharmacokinetic-pharmacodynamic modelling in the drug discovery process.
abstract: 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.
authors.affiliation: Genentech Inc, South San Francisco, CA, USA. choo.edna@gene.com
authors.forename: Edna F
authors.initials: EF
authors.lastname: Choo
authors.forename: Bruno
authors.initials: B
authors.lastname: Alicke
authors.forename: Jason
authors.initials: J
authors.lastname: Boggs
authors.forename: Vikki
authors.initials: V
authors.lastname: Dinkel
authors.forename: Stephen
authors.initials: S
authors.lastname: Gould
authors.forename: Jonas
authors.initials: J
authors.lastname: Grina
authors.forename: Kristina
authors.initials: K
authors.lastname: West
authors.forename: Kapil
authors.initials: K
authors.lastname: Menghrajani
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Ran
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
authors.forename: Steve
authors.initials: S
authors.lastname: Wenglowsky
mesh_terms: D000818:Animals; D019540:Area Under Curve; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000097:blood / Q000473:pathology; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D008297:Male; D051379:Mice; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf