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Application of a systems pharmacology model to understand the complex PK/PD behavior of the anti-asthmatic drug Zileuton in terms of its mechanism of action

Aim of the project:

To identify the physiological mechanisms underlying the complex PK/PD behavior observed in clinical trials of Zileuton: (i) no differences in FEV1 response resulting from a single administration of 400 or 600 mg of Zileuton, (ii) the emergence of differences in FEV1 response resulting from QID administration of 400 or 600 mg of Zileuton after the eighth day. 

Results:

A systems pharmacology model was developed integrating all known in vitro, in vivo, and clinical data on the relevant components of 5LO-mediated inflammatory pathophysiology and possible regulatory mechanisms involved in the response at the intracellular, cellular, and organism levels. This mathematical model contained the following components: (i) a cell dynamics model of eosinophil (EO) maturation, migration, activation, and death; (ii) a detailed biochemical model of 5-LO function; (iii) a semimechanistic model of leukotriene (LT) biosynthesis in leukocytes; (iv) a biophysical model of bronchoconstriction; and (v) a PK model of Zileuton and its inhibition of the intracellular 5LO pathway. The physiological mechanisms underlying the complex PK/PD behavior observed in clinical trials were identified on the basis of the model.

Initiator of the project:

Pfizer

Download presentation:

anti-asthmatic_drugs.pdf