Bruton's tyrosine kinase (BTK) plays a critical role in the development, differentiation and proliferation of B-lineage cells, making it an attractive target for the treatment of rheumatoid arthritis. The objective of this study was to evaluate the anti-arthritis effect of GDC-0834 (R-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), a potent and selective BTK inhibitor, and characterize the relationship between inhibition of BTK phosphorylation (pBTK) and efficacy. GDC-0834 inhibited BTK with an in vitro IC50 of 5.9 nM and 6.4 nM in biochemical and cellular assays, respectively, and in vivo IC50 of 1.1 and 5.6 µM in mouse and rat, respectively. Administration of GDC-0834 (30 to 100 mg/kg) in a rat collagen-induced arthritis (CIA) model resulted in dose-dependent decrease of ankle swelling and reduction of morphologic pathology. An integrated disease progression pharmacokinetic/pharmacodynamic model where efficacy is driven by pBTK inhibition was fit to ankle diameter time course data. This model incorporated a transit model to characterize non-drug related decreases in ankle swelling occurring at later stages of disease progression in CIA rats. The time-course of ankle swelling in vehicle animals was described well by the base model. Simultaneous fitting of data from vehicle and GDC-0834 treated groups showed that overall 73% inhibition of pBTK was needed to decrease the rate constant describing the ankle swelling increase (kin) by half. These findings suggest a high degree of pBTK inhibition is required for maximal activity of the pathway on inflammatory arthritis in rats.
- Received March 11, 2011.
- Revision received April 21, 2011.
- Accepted April 25, 2011.
- The American Society for Pharmacology and Experimental Therapeutics