Jump to main content
Jump to site search
PLANNED MAINTENANCE Close the message box

Scheduled maintenance upgrade on Thursday 4th of May 2017 from 8.00am to 9.00am (BST).

During this time our websites will be offline temporarily. If you have any questions please use the feedback button on this page. We apologise for any inconvenience this might cause and thank you for your patience.



A quantitative mechanistic PK/PD model directly connects Btk target engagement and in vivo efficacy

Author affiliations

Abstract

Correlating target engagement with in vivo drug activity remains a central challenge in efforts to improve the efficiency of drug discovery. Previously we described a mechanistic pharmacokinetic–pharmacodynamic (PK/PD) model that used drug–target binding kinetics to successfully predict the in vivo efficacy of antibacterial compounds in models of Pseudomonas aeruginosa and Staphylococcus aureus infection. In the present work we extend this model to quantitatively correlate the engagement of Bruton's tyrosine kinase (Btk) by the covalent inhibitor CC-292 with the ability of this compound to reduce ankle swelling in an animal model of arthritis. The modeling studies include the rate of Btk turnover and reveal the vulnerability of Btk to engagement by CC-292.

Graphical abstract: A quantitative mechanistic PK/PD model directly connects Btk target engagement and in vivo efficacy

Back to tab navigation
Please wait while Download options loads

Supplementary files

Publication details

The article was received on 26 Jul 2016, accepted on 10 Mar 2017 and first published on 14 Mar 2017


Article type: Edge Article
DOI: 10.1039/C6SC03306G
Citation: Chem. Sci., 2017, Advance Article
  • Open access: Creative Commons BY-NC license
  •   Request permissions

    A quantitative mechanistic PK/PD model directly connects Btk target engagement and in vivo efficacy

    F. Daryaee, Z. Zhang, K. R. Gogarty, Y. Li, J. Merino, S. L. Fisher and P. J. Tonge, Chem. Sci., 2017, Advance Article , DOI: 10.1039/C6SC03306G

Search articles by author