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Issue 5, 2017
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A quantitative mechanistic PK/PD model directly connects Btk target engagement and in vivo efficacy

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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

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Supplementary files

Article information


Submitted
26 Jul 2016
Accepted
10 Mar 2017
First published
14 Mar 2017

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2017,8, 3434-3443
Article type
Edge Article

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, 8, 3434
DOI: 10.1039/C6SC03306G

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