PT  - JOURNAL ARTICLE
AU  - Lichuan Liu
AU  - Jason S. 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 C. Davis, Jr.
AU  - X. Charlene Liao
AU  - Joseph W. Lubach
AU  - Alan Deese
AU  - C. Gregory Sowell
AU  - Kevin S. Currie
AU  - Wendy B. Young
AU  - S. Cyrus Khojasteh
AU  - Cornelis E. C. A. Hop
AU  - Harvey Wong
TI  - Significant Species Difference in Amide Hydrolysis of GDC-0834, a Novel Potent and Selective Bruton's Tyrosine Kinase Inhibitor
AID  - 10.1124/dmd.111.040840
DP  - 2011 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 1840--1849
VI  - 39
IP  - 10
4099  - http://dmd.aspetjournals.org/content/39/10/1840.short
4100  - http://dmd.aspetjournals.org/content/39/10/1840.full
SO  - Drug Metab Dispos2011 Oct 01; 39
AB  - (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 (GDC-0834) is a potent and selective inhibitor of Bruton's tyrosine kinase (BTK), investigated as a potential treatment for rheumatoid arthritis. 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 investigational new drug strategy, in which 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 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 that in 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- to 169-fold higher than observed in rat, dog, and monkey.