title: Quantitative Systems Pharmacology Model to Predict the Effects of Commonly Used Anticoagulants on the Human Coagulation Network.
abstract: Warfarin is the anticoagulant of choice for venous thromboembolism (VTE) treatment, although its suppression of the endogenous clot-dissolution complex APC:PS may ultimately lead to longer time-to-clot dissolution profiles, resulting in increased risk of re-thrombosis. This detrimental effect might not occur during VTE treatment using other anticoagulants, such as rivaroxaban or enoxaparin, given their different mechanisms of action within the coagulation network. A quantitative systems pharmacology model was developed describing the coagulation network to monitor clotting factor levels under warfarin, enoxaparin, and rivaroxaban treatment. The model allowed for estimation of all factor rate constants and production rates. Predictions of individual coagulation factor time courses under steady-state warfarin, enoxaparin, and rivaroxaban treatment reflected the suppression of protein C and protein S under warfarin compared to rivaroxaban and enoxaparin. The model may be used as a tool during clinical practice to predict effects of anticoagulants on individual clotting factor time courses and optimize antithrombotic therapy.
authors.affiliation: Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, Florida, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hartmann
authors.affiliation: Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, Florida, USA.
authors.forename: K
authors.initials: K
authors.lastname: Biliouris
authors.affiliation: Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, Florida, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Lesko
authors.affiliation: University of Schleswig-Holstein, Institute of Clinical Chemistry, Thrombosis and Hemostasis Treatment Center, Campus Kiel and Lübbeck, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Nowak-Göttl
authors.affiliation: Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, Florida, USA. mtrame@cop.ufl.edu.
authors.forename: M N
authors.initials: MN
authors.lastname: Trame
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects* / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D017984:Enoxaparin / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011486:Protein C / Q000378:metabolism*; D017293:Protein S / Q000378:metabolism*; D000069552:Rivaroxaban / Q000009:adverse effects / Q000494:pharmacology; D054556:Venous Thromboembolism / Q000188:drug therapy* / Q000378:metabolism; D014859:Warfarin / Q000009:adverse effects / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D017984:Enoxaparin; D011486:Protein C; D017293:Protein S; D014859:Warfarin; D000069552:Rivaroxaban