A mechanistic pharmacodynamic model of IRAK-4 drug inhibition in the Toll-like receptor pathway

被引:2
作者
Nolan, Ryan P. [1 ]
Bree, Andrea G. [2 ]
Zutshi, Anup [1 ]
机构
[1] Pfizer Global Res & Dev, Pharmacokinet Dynam & Metab, Cambridge, MA 02140 USA
[2] Pfizer Global Res & Dev, Inflammat & Remodeling, Cambridge, MA 02140 USA
关键词
TLR-4; IRAK-4; IRAK-M; LPS tolerance; Systems pharmacology model; TUMOR-NECROSIS-FACTOR; HUMAN ENDOTOXEMIA; NEGATIVE REGULATION; HUMAN MONOCYTES; DOWN-REGULATION; TLR EXPRESSION; WHOLE-BLOOD; TOLERANCE; MACROPHAGES; RESPONSES;
D O I
10.1007/s10928-013-9334-0
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The TLR pathway has been implicated in the pathogenesis of numerous diseases. IRAK-4 is integral to this pathway, making it a viable target for therapeutic intervention. This paper describes the application of a mechanistic pharmacodynamic model to assess the impact of IRAK-4 inhibition on the TLR-4 pathway. The model uses a minimal number of rate equations, molecular species, and parameters to characterize TLR signal transduction biology, including ligand-receptor interaction, protein complex formation, protein phosphorylation, negative regulation, and cytokine production. The model successfully reproduces the dynamic responses of TNF alpha to LPS stimulation, the tolerance to sequential LPS bolus dosing, the burst following a LPS bolus or infusion, and the modulation of pathway biomarkers following administration of an IRAK-4 inhibitor. Drug dosing schemes are evaluated for simulated disease states. The results emphasize the significance of LPS kinetics on response dynamics and the utility of a mechanistic model to help translate drug efficacy.
引用
收藏
页码:609 / 622
页数:14
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