Demin2013 - PKPD behaviour - 5-Lipoxygenase inhibitors

Demin2013 - PKPD behaviour - 5-Lipoxygenase
inhibitors

This model is described in the article:

Systems pharmacology models
can be used to understand complex
pharmacokinetic-pharmacodynamic behavior: an example using
5-lipoxygenase inhibitors.

Demin O, Karelina T, Svetlichniy D,
Metelkin E, Speshilov G, Demin O Jr, Fairman D, van der Graaf PH,
Agoram BM.
CPT Pharmacometrics Syst Pharmacol
2013; 2: e74
Abstract:

Zileuton, a 5-lipoxygenase (5LO) inhibitor, displays complex
pharmaokinetic (PK)-pharmacodynamic (PD) behavior. Available
clinical data indicate a lack of dose-bronchodilatory response
during initial treatment, with a dose response developing after
~1-2 weeks. We developed a quantitative systems pharmacology
(QSP) model to understand the mechanism behind this phenomenon.
The model described the release, maturation, and trafficking of
eosinophils into the airways, leukotriene synthesis by the 5LO
enzyme, leukotriene signaling and bronchodilation, and the PK
of zileuton. The model provided a plausible explanation for the
two-phase bronchodilatory effect of zileuton-the short-term
bronchodilation was due to leukotriene inhibition and the
long-term bronchodilation was due to inflammatory cell
infiltration blockade. The model also indicated that the
theoretical maximum bronchodilation of both 5LO inhibition and
leukotriene receptor blockade is likely similar. QSP modeling
provided interesting insights into the effects of leukotriene
modulation.CPT: Pharmacometrics & Systems Pharmacology
(2013) 2, e74; doi:10.1038/psp.2013.49; advance online
publication 11 September 2013.

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