GDC-0834 is a potent and selective Bruton's tyrosine kinase (Btk) inhibitor, The IC50 values in biochemical and cellular assays is 5.9 and 6.4 nM. The in vivo IC50 values in mouse and rat are 1.1 and 5.6 μM, respectively [1]. B cell antigen receptor (BCR) stimulation phosphorylated and activated Btk. Btk gene defects result in a disease named as X-linked agammaglobulinemia which profoundly decreased mature B cells due to a block in B cell development [2].
In vivo: In a rat collagen-induced arthritis (CIA) model, administration of GDC-0834 (30-100 mg/kg) model resulted in a dose-dependent decrease of ankle swelling and reduction of morphologic pathology [1].In PXB chimeric mice with humanized liver, GDC-0834 exhibited low clearance. in most samples from the cohorts dosed orally at 35 and 105 mg GDC-0834, plasma concentrations of GDC-0834 in humans were below the limit of quantitation (<1 ng/ml). High interest in a BTK inhibitor for clinical evaluation and uncertainty in human pharmacokinetic prediction prompted an investigational new drug strategy, in which GDC-0834 was rapidly advanced to a single-dose human clinical trial [3].
References:
[1]. Liu L, Di Paolo J, Barbosa J, et al. Antiarthritis effect of a novel Bruton's tyrosine kinase (BTK) inhibitor in rat collagen-induced arthritis and mechanism-based pharmacokinetic/pharmacodynamic modeling: relationships between inhibition of BTK phosphorylation and efficacy[J]. Journal of Pharmacology and Experimental Therapeutics, 2011, 338(1): 154-163.
[2]. Takata M, Kurosaki T. A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2[J]. The Journal of experimental medicine, 1996, 184(1): 31-40.
[3]. Liu L, Halladay J S, Shin Y, et al. Significant species difference in amide hydrolysis of GDC-0834, a novel potent and selective Bruton's tyrosine kinase inhibitor[J]. Drug Metabolism and Disposition, 2011, 39(10): 1840-1849.