Can systems modeling approach be used to understand complex PK-PD relationships? A case study of 5-lipoxygenase inhibition by zileuton
Tatiana Karelina(1), Oleg Demin(1), Kirill Zhudenkov(1), Dmitry Svetlichny(1), Oleg Demin Jr(1,3), David Fairman(2), and Balaji Agoram(2)
1: Institute for Systems Biology; Moscow 2: Pfizer Research, Allergy and Respiratory, Sandwich UK. 3: Corresponding author: firstname.lastname@example.org
Motivation: Systems modeling approaches are seen as the next step in the evolution of mechanism-based pharmacokinetic-pharmacodynamic (PKPD) modeling. However, while some recent publications have highlighted development of such models, few examples exist in literature on the successful application of this novel methodology within the drug development setting. We report the exploration of the hypothesis that complex literature-based systems models can be developed and applied during drug discovery and development of 5-lipoxygenase (5LO) inhibitors for asthma. Our initial interest focused on the human dose/time/effect (FEV1) relationship of a marketed 5LO inhibitor (Zileuton).
- To develop a minimal systems model of 5LO inhibition and FEV1 regulation using literature data.
- To evaluate the possible mechanisms underlying the observed complex relationship between the PK and PD (FEV1) of Zileuton.
- Use the model to test alternate medical hypotheses.
Methods: A systems model was developed integrating all known in vitro, in vivo and clinical data on the relevant components of 5LO-mediated inflammatory patho-physiology and possible regulatory mechanisms involved in the response at the intracellular, cellular and organism levels. This mathematical model contained the following components (i) cell dynamics model of eosinphil (EO) maturation, migration, activation and death, (ii) detailed biochemical model of 5-LO operation, (iii) semi-mechanistic model of leukotriene (LT) biosynthesis in leukocytes, (iv) biophysical model of bronchoconstriction, and (v) PK model of Zileuton and its inhibition of the intracellular 5LO pathway. All model parameters were estimated on the basis of available literature data.
Results: Multiple hypotheses were generated using the model to explain the observed delayed dose-response to zileuton administration in asthmatic subjects. Simulations using the model indicated that:
- Acute bronchodilation after zileuton administration was due to direct inhibition of LT synthesis. Doses of 400 and 600 mg maximally achieved this inhibition hence no dose-response is observed.
- In the asthmatic state high levels of activated Inflammatory cells in the lung are driven by two positive feedback mechanisms via LT activation of EO and IL-5 induced cellular proliferation and activation.
- Sustained high levels of inhibition of LT synthesis (>85%) are required to interrupt these positive feedback mechanisms and so reduce the number of resident inflammatory cells. Thus leading to reduced bronchodilatory stimuli (LT and non LT such as histamine) and subsequent chronic bronchodilation at doses greater than 400 mg.
- The delay in the observation of dose-response is characteristic of EO cell lifespan in the airways.
- As observed in literature, model predicts that 5LO inhibition has inherently higher efficacy potential than LT receptor antagonism.
Conclusions: A systems model of the 5LO pathway and its role in asthma pathophysiology was developed and was successful in helping to understand the complex PK-PD relationship of zileuton. The model can be used in the discovery setting to better understand the role of various therapeutic interventions in asthma and potentially impact the design of early clinical studies of new candidates.