title: Using a Systems Pharmacology Model of the Blood Coagulation Network to Predict the Effects of Various Therapies on Biomarkers.
abstract: A number of therapeutics have been developed or are under development aiming to modulate the coagulation network to treat various diseases. We used a systems model to better understand the effect of modulating various components on blood coagulation. A computational model of the coagulation network was built to match in-house in vitro thrombin generation and activated Partial Thromboplastin Time (aPTT) data with various concentrations of recombinant factor VIIa (FVIIa) or factor Xa added to normal human plasma or factor VIII-deficient plasma. Sensitivity analysis applied to the model revealed that lag time, peak thrombin concentration, area under the curve (AUC) of the thrombin generation profile, and aPTT show different sensitivity to changes in coagulation factors' concentrations and type of plasma used (normal or factor VIII-deficient). We also used the model to explore how variability in concentrations of the proteins in coagulation network can impact the response to FVIIa treatment.
authors: Pharmacometrics, Global Innovative Pharma Business (GIPB), Pfizer Inc. Cambridge, Massachusetts, USA.
authors: S
authors: S
authors: Nayak
authors: Quantitative Clinical Sciences, PharmaTherapeutics Clinical R&D, Pfizer Inc. Cambridge, Massachusetts, USA.
authors: D
authors: D
authors: Lee
authors: Rare Disease Research Unit Pfizer Inc. Cambridge, Massachusetts, USA.
authors: S
authors: S
authors: Patel-Hett
authors: Rare Disease Research Unit Pfizer Inc. Cambridge, Massachusetts, USA.
authors: D D
authors: DD
authors: Pittman
authors: Pharmacometrics, Global Innovative Pharma Business (GIPB), Pfizer Inc. Cambridge, Massachusetts, USA.
authors: S W
authors: SW
authors: Martin
authors: Quantitative Clinical Sciences, PharmaTherapeutics Clinical R&D, Pfizer Inc. Cambridge, Massachusetts, USA.
authors: A C
authors: AC
authors: Heatherington
authors: Pharmacokinetics, Dynamics and Metabolism, New Biological Entities, Pfizer Inc. Cambridge, Massachusetts, USA.
authors: P
authors: P
authors: Vicini
authors: Quantitative Clinical Sciences, PharmaTherapeutics Clinical R&D, Pfizer Inc. Cambridge, Massachusetts, USA.
authors: F
authors: F
authors: Hua