TY - JOUR T1 - Significant Species Difference in Amide Hydrolysis of GDC-0834, a Novel Potent and Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.040840 SP - dmd.111.040840 AU - Lichuan Liu AU - Jason Halladay AU - Young Shin AU - Susan Wong AU - Melis Coraggio AU - Hank La AU - Matthew Baumgardner AU - Hoa Le AU - Sashi Gopaul AU - Jason Boggs AU - Peter Kuebler AU - John Davis AU - Charlene Liao AU - Joseph Lubach AU - Alan Deese AU - Gregory Sowell AU - Kevin Currie AU - Wendy Young AU - Cyrus Khojasteh AU - Cornelis Hop AU - Harvey Wong Y1 - 2011/01/01 UR - http://dmd.aspetjournals.org/content/early/2011/07/08/dmd.111.040840.abstract N2 - GDC-0834 is a potent and selective inhibitor of Bruton's tyrosine kinase (BTK) investigated as a potential treatment for rheumatoid arthritis (RA). In vitro metabolite identification studies in hepatocytes revealed predominant formation of an inactive metabolite (M1) via amide hydrolysis in human. The formation of M1 appeared to be NADPH-independent in human liver microsomes. M1 was found in only minor to moderate quantities in plasma from preclinical species dosed with GDC-0834. Human clearance predictions using various methodologies resulted in estimates ranging from low to high. In addition, GDC-0834 exhibited low clearance in PXB chimeric mice with humanized liver. Uncertainty in human pharmacokinetic prediction and high interest in a BTK inhibitor for clinical evaluation prompted an IND strategy where GDC-0834 was rapidly advanced to a single dose human clinical trial. GDC-0834 plasma concentrations in humans were below the limit of quantitation (< 1 ng/mL) in most samples from the cohorts dosed orally at 35 mg and 105 mg. In contrast, substantial plasma concentrations of M1 were observed. In human plasma and urine, only M1 and its sequential metabolites were identified. The formation kinetics of M1 was evaluated in rat, dog, monkey and human liver microsomes in the absence of NADPH. The maximum rate of M1 formation (Vmax) was substantially higher in human compared with other species. In contrast, the Michaelis-Menten constant (Km) was comparable among species. Intrinsic clearance (Vmax/Km) of GDC-0834 from M1 formation in human was 23 - 169 fold higher than observed in rat, dog and monkey. ER -