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

• Published in: Journal of pharmacokinetics and pharmacodynamics 2013-10, Vol.40 (5), p.609-622
• Main Authors: Nolan, Ryan P., Bree, Andrea G., Zutshi, Anup
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Dose-Response Relationship, Drug; Humans; Interleukin-1 Receptor-Associated Kinases - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Original Paper; Pharmacology/Toxicology; Pharmacy; Signal Transduction - drug effects; Toll-Like Receptors - metabolism; Tumor Necrosis Factor-alpha - metabolism; Veterinary Medicine/Veterinary Science
• ISSN: 1567-567X; 1573-8744
• DOI: 10.1007/s10928-013-9334-0

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 TNFα 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.