Scale reduction of a systems coagulation model with an application to modeling pharmacokinetic-pharmacodynamic data

A Gulati; G K Isbister; S B Duffull

doi:10.1038/psp.2013.67

Scale reduction of a systems coagulation model with an application to modeling pharmacokinetic-pharmacodynamic data

CPT Pharmacometrics Syst Pharmacol. 2014 Jan 8;3(1):e90. doi: 10.1038/psp.2013.67.

Authors

A Gulati¹, G K Isbister², S B Duffull¹

Affiliations

¹ School of Pharmacy, University of Otago, Dunedin, New Zealand.
² 1] Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle, New South Wales, Australia [2] Discipline of Clinical Pharmacology, University of Newcastle, New South Wales, Australia.

Abstract

Bridging systems biology and pharmacokinetics-pharmacodynamics has resulted in models that are highly complex and complicated. They usually contain large numbers of states and parameters and describe multiple input-output relationships. Based on any given data set relating to a specific input-output process, it is possible that some states of the system are either less important or have no influence at all. In this study, we explore a simplification of a systems pharmacology model of the coagulation network for use in describing the time course of fibrinogen recovery after a brown snake bite. The technique of proper lumping is used to simplify the 62-state systems model to a 5-state model that describes the brown snake venom-fibrinogen relationship while maintaining an appropriate mechanistic relationship. The simplified 5-state model explains the observed decline and recovery in fibrinogen concentrations well. The techniques used in this study can be applied to other multiscale models.