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 (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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.040840.
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ABBREVIATIONS:
- BTK
- Bruton's tyrosine kinase
- RA
- rheumatoid arthritis
- GDC-0834
- (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
- PK
- pharmacokinetic(s)
- SCID
- severe combined immunodeficiency disease
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- DMEM
- Dulbecco's modified Eagle's medium
- MLP
- maximum lifespan potential
- IVIVE
- in vitro/in vivo extrapolation
- LM
- liver microsome(s)
- AUC
- area under the concentration-time curve
- P450
- cytochrome P450
- IND
- investigational new drug.
- Received May 23, 2011.
- Accepted July 6, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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