Development of a Quantitative Systems Pharmacology Model of the Blood Coagulation Network & its Application to Clinical Programs

A number of therapeutics have been developed or are under development aiming to modulate the coagulation network to treat various diseases such as Hemophilia. We developed a quantitative systems pharmacology model to better understand the effect of modulating various components on blood coagulation. The model of the coagulation network was composed of mass balance reactions and was optimized to describe ex vivo biomarkers including thrombin generation assay (TGA) parameters, activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) and in vivo biomarkers under non-bleeding conditions including prothrombin fragment 1+2 (PF1+2), D-dimer and thrombin anti-thrombin III complex (TAT). Protein synthesis and degradation were turned on to describe the in vivo model, but were turned off when describing ex vivo biomarker changes. Platelet activation-dependent reactions also had different reaction rates for the ex vivo vs. in vivo biomarkers to reflect differences in assay conditions. Both in house data with various concentrations of recombinant factor VIIa (FVIIa) or factor Xa added to normal human plasma or factor VIII-deficient plasma and literature data were used for estimating model parameters. Sensitivity analysis applied to the model revealed that biomarkers show different sensitivity to changes in coagulation factors' concentrations and the type of plasma used (normal or factor VIII-deficient).The model was validated through a comparison between clinical data from the recently concluded Pfizer study in Hemophilia subjects. We observed good agreement between clinical observations and model predicted results, providing us with further confidence to apply the model in dose selection strategies for subsequent phases. Finally, we applied the model to predict how variability in concentrations of the proteins in coagulation network may impact the response to FVIIa treatment in Hemophilia subjects.