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Research ArticleInflammation, Immunopharmacology, and Asthma

Antiarthritis Effect of a Novel Bruton's Tyrosine Kinase (BTK) Inhibitor in Rat Collagen-Induced Arthritis and Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling: Relationships between Inhibition of BTK Phosphorylation and Efficacy

Lichuan Liu, Julie Di Paolo, Jim Barbosa, Hong Rong, Karin Reif and Harvey Wong
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 154-163; DOI: https://doi.org/10.1124/jpet.111.181545
Lichuan Liu
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Julie Di Paolo
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Jim Barbosa
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Hong Rong
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Karin Reif
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Harvey Wong
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Abstract

Bruton's tyrosine kinase (BTK) plays a critical role in the development, differentiation, and proliferation of B-lineage cells, making it an attractive target for the treatment of rheumatoid arthritis. The objective of this study was to evaluate the antiarthritis effect of 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], a potent and selective BTK inhibitor, and characterize the relationship between inhibition of BTK phosphorylation (pBTK) and efficacy. GDC-0834 inhibited BTK with an in vitro IC50 of 5.9 and 6.4 nM in biochemical and cellular assays, respectively, and in vivo IC50 of 1.1 and 5.6 μM in mouse and rat, respectively. Administration of GDC-0834 (30–100 mg/kg) in a rat collagen-induced arthritis (CIA) model resulted in a dose-dependent decrease of ankle swelling and reduction of morphologic pathology. An integrated disease progression pharmacokinetic/pharmacodynamic model where efficacy is driven by pBTK inhibition was fit to ankle-diameter time-course data. This model incorporated a transit model to characterize nondrug-related decreases in ankle swelling occurring at later stages of disease progression in CIA rats. The time course of ankle swelling in vehicle animals was described well by the base model. Simultaneous fitting of data from vehicle- and GDC-0834-treated groups showed that overall 73% inhibition of pBTK was needed to decrease the rate constant describing the ankle swelling increase (kin) by half. These findings suggest a high degree of pBTK inhibition is required for maximal activity of the pathway on inflammatory arthritis in rats.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.181545.

  • ABBREVIATIONS:

    RA
    rheumatoid arthritis
    BTK
    Bruton's tyrosine kinase
    pBTK
    BTK (auto)phosphorylation
    CIA
    collagen-induced arthritis
    PK
    pharmacokinetic
    PD
    pharmacodynamic
    CV
    coefficient of variation
    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
    LC/MS/MS
    liquid chromatography-tandem mass spectrometry
    IL
    interleukin
    QD
    once daily
    Q2D
    every other day
    AUC
    area under the curve
    CGI1746
    4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide.

  • Received March 11, 2011.
  • Accepted April 25, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleInflammation, Immunopharmacology, and Asthma

Antiarthritis Effect of a Novel Bruton's Tyrosine Kinase (BTK) Inhibitor in Rat Collagen-Induced Arthritis and Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling: Relationships between Inhibition of BTK Phosphorylation and Efficacy

Lichuan Liu, Julie Di Paolo, Jim Barbosa, Hong Rong, Karin Reif and Harvey Wong
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 154-163; DOI: https://doi.org/10.1124/jpet.111.181545

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Research ArticleInflammation, Immunopharmacology, and Asthma

Antiarthritis Effect of a Novel Bruton's Tyrosine Kinase (BTK) Inhibitor in Rat Collagen-Induced Arthritis and Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling: Relationships between Inhibition of BTK Phosphorylation and Efficacy

Lichuan Liu, Julie Di Paolo, Jim Barbosa, Hong Rong, Karin Reif and Harvey Wong
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 154-163; DOI: https://doi.org/10.1124/jpet.111.181545
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