Development of a Quantitative Systems Pharmacology Model of the Blood
Coagulation Network & its Application to Clinical Programs
by Satyaprakash Nayak, Pharmacometrician, Systems Biologist at Pfizer
September 16, 2015, 1:00 to 2:00 pm EDT
Abstract: 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 plasma1,2 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 subjects2. 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.
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