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Population PK-PD model for tolerance evaluation to the p38 MAP kinase inhibitor BCT197

De Buck, Stefan and Hueber, Wolfgang and Vitaliti Garami, Alessandra and Straube, Frank and Emotte, Corinne and Bruin, Gerardus and Woessner, Ralph (2015) Population PK-PD model for tolerance evaluation to the p38 MAP kinase inhibitor BCT197. Pharmacometrics and System Biology.

Abstract

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 treatment of chronic inflammation. It was the objective of this study to characterize the population pharmacokinetics (PK) of BCT197 in heathy volunteers and to examine the relationship between BCT197 exposure and pharmacodynamics (PD) measured as inhibition of ex-vivo LPS-induced TNF, a downstream surrogate marker of p38. 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 TNF was counteracted, at least partly, 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 revealed that an intermittent regimen may offer clinical benefit over continuous dosing, by limiting the potential impact of tolerance development.

Item Type: Article
Keywords: p38 MAPK kinase, COPD, BCT197, population pharmacokinetics, TNFα
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/25684

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