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Population PK‐PD Model for Tolerance Evaluation to the p38 MAP Kinase Inhibitor BCT197

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 t...

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Autores principales: De Buck, S, Hueber, W, Vitaliti, A, Straube, F, Emotte, C, Bruin, G, Woessner, R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759708/
https://www.ncbi.nlm.nih.gov/pubmed/26904383
http://dx.doi.org/10.1002/psp4.12037
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author De Buck, S
Hueber, W
Vitaliti, A
Straube, F
Emotte, C
Bruin, G
Woessner, R
author_facet De Buck, S
Hueber, W
Vitaliti, A
Straube, F
Emotte, C
Bruin, G
Woessner, R
author_sort De Buck, S
collection PubMed
description 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.
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spelling pubmed-47597082016-02-22 Population PK‐PD Model for Tolerance Evaluation to the p38 MAP Kinase Inhibitor BCT197 De Buck, S Hueber, W Vitaliti, A Straube, F Emotte, C Bruin, G Woessner, R CPT Pharmacometrics Syst Pharmacol Original Articles 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. John Wiley and Sons Inc. 2015-11-09 2015-12 /pmc/articles/PMC4759708/ /pubmed/26904383 http://dx.doi.org/10.1002/psp4.12037 Text en © 2015 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
De Buck, S
Hueber, W
Vitaliti, A
Straube, F
Emotte, C
Bruin, G
Woessner, R
Population PK‐PD Model for Tolerance Evaluation to the p38 MAP Kinase Inhibitor BCT197
title Population PK‐PD Model for Tolerance Evaluation to the p38 MAP Kinase Inhibitor BCT197
title_full Population PK‐PD Model for Tolerance Evaluation to the p38 MAP Kinase Inhibitor BCT197
title_fullStr Population PK‐PD Model for Tolerance Evaluation to the p38 MAP Kinase Inhibitor BCT197
title_full_unstemmed Population PK‐PD Model for Tolerance Evaluation to the p38 MAP Kinase Inhibitor BCT197
title_short Population PK‐PD Model for Tolerance Evaluation to the p38 MAP Kinase Inhibitor BCT197
title_sort population pk‐pd model for tolerance evaluation to the p38 map kinase inhibitor bct197
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759708/
https://www.ncbi.nlm.nih.gov/pubmed/26904383
http://dx.doi.org/10.1002/psp4.12037
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