Open AccessPopulation PK‐PD Model for Tolerance Evaluation to the p38 MAP Kinase Inhibitor BCT197
Author(s) -
De Buck S,
Hueber W,
Vitaliti A,
Straube F,
Emotte C,
Bruin G,
Woessner R
Publication year - 2015
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12037
Subject(s) - pharmacology , pharmacodynamics , p38 mitogen activated protein kinases , population , pharmacokinetics , tumor necrosis factor alpha , medicine , inflammation , dosing , ex vivo , kinase , in vivo , protein kinase a , immunology , biology , microbiology and biotechnology , environmental health
The p38 mitogen‐activated protein kinase (p38) is a key signaling pathway involved in regulation of inflammatory cytokines. Unexpectedly, several clinical studies using p38 inhibitors found no convincing clinical efficacy in the treatment of chronic inflammation. It was the objective of this study to characterize the population pharmacokinetics (PK) of BCT197 in healthy volunteers and to examine the relationship between BCT197 exposure and pharmacodynamics (PD) measured as inhibition of ex vivo lipopolysaccharide (LPS)‐induced tumor necrosis factor alpha (TNFα), a downstream marker of p38 activity. PK was characterized using a two‐compartment model with mixed‐order absorption and limited‐capacity tissue binding. The PK‐PD relationship revealed that suppression of TNFα was partly offset over time, despite continuous drug exposure. This may indicate a mechanism by which the inflammatory response acquires the ability to bypass p38. Simulations of posology dependence in drug effect suggest that an intermittent regimen may offer clinical benefit over continuous dosing and limit the impact of tolerance development.