Systems Pharmacology Models Can Be Used to Understand Complex Pharmacokinetic‐Pharmacodynamic Behavior: An Example Using 5‐Lipoxygenase Inhibitors

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.

Evaluating Systems Pharmacology Models Is Different From Evaluating Standard Pharmacokinetic–Pharmacodynamic Models

“…Justification of a systems model on the basis of plausible structures and parameter values based on prior mechanistic knowledge and qualitative comparison of prediction vs. observations all constitute subjective criteria and should be acceptable for systems model justification. For example, in the study by Demin et al ., 1 the predicted bronchodilation for zileuton was 20–25% vs. ~15% observed. However, the conclusions were still considered valid because of a weight‐of‐evidence approach: accurate prediction of biomarker and bronchodilation changes with montelukast, the known assumptions in the model, and the qualitative rather than quantitative objective of the effort.…”

BioModels: Content, Features, Functionality, and Use

“…There is an increasing number of research articles where the mechanism underlying the treatment (side‐) effect, resistance to drug compounds, etc., are investigated using Systems Pharmacology modeling approaches (“Demin2013 – PKPD behavior ‐ 5‐Lipoxygenase inhibitors” (BIOMD0000000490), “Faratian2009 – Role of PTEN in resistance to trastuzumab” (BIOMD0000000424), Palmer et al …”

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