title: Significant species difference in amide hydrolysis of GDC-0834, a novel potent and selective Bruton's tyrosine kinase inhibitor.
abstract: (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 (V(max)) was substantially higher in human compared with that in other species. In contrast, the Michaelis-Menten constant (K(m)) was comparable among species. Intrinsic clearance (V(max)/K(m)) of GDC-0834 from M1 formation in human was 23- to 169-fold higher than observed in rat, dog, and monkey.
authors: Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, MS# 412a, South San Francisco, CA 94080, USA. liu.lichuan@gene.com
authors: Lichuan
authors: L
authors: Liu
authors: Jason S
authors: JS
authors: Halladay
authors: Young
authors: Y
authors: Shin
authors: Susan
authors: S
authors: Wong
authors: Melis
authors: M
authors: Coraggio
authors: Hank
authors: H
authors: La
authors: Matthew
authors: M
authors: Baumgardner
authors: Hoa
authors: H
authors: Le
authors: Sashi
authors: S
authors: Gopaul
authors: Jason
authors: J
authors: Boggs
authors: Peter
authors: P
authors: Kuebler
authors: John C
authors: JC
authors: Davis
authors: X Charlene
authors: XC
authors: Liao
authors: Joseph W
authors: JW
authors: Lubach
authors: Alan
authors: A
authors: Deese
authors: C Gregory
authors: CG
authors: Sowell
authors: Kevin S
authors: KS
authors: Currie
authors: Wendy B
authors: WB
authors: Young
authors: S Cyrus
authors: SC
authors: Khojasteh
authors: Cornelis E C A
authors: CE
authors: Hop
authors: Harvey
authors: H
authors: Wong
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000577:Amides / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D017321:Clinical Trials, Phase I as Topic; D004285:Dogs; D004311:Double-Blind Method; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011744:Pyrimidinones / Q000378:metabolism* / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013876:Thiophenes / Q000378:metabolism* / Q000493:pharmacokinetics*
chemical_list: D000577:Amides; C560621: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; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D013876:Thiophenes; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse