RT Journal Article SR Electronic 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 FD American Society for Pharmacology and Experimental Therapeutics SP dmd.111.040840 DO 10.1124/dmd.111.040840 A1 Lichuan Liu A1 Jason Halladay A1 Young Shin A1 Susan Wong A1 Melis Coraggio A1 Hank La A1 Matthew Baumgardner A1 Hoa Le A1 Sashi Gopaul A1 Jason Boggs A1 Peter Kuebler A1 John Davis A1 Charlene Liao A1 Joseph Lubach A1 Alan Deese A1 Gregory Sowell A1 Kevin Currie A1 Wendy Young A1 Cyrus Khojasteh A1 Cornelis Hop A1 Harvey Wong YR 2011 UL http://dmd.aspetjournals.org/content/early/2011/07/08/dmd.111.040840.abstract AB 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.