Burghaus2014 - Simulating blood coagulation factor Xa inhibitors
Mathematical model of blood coagulation factors II, VII, IX and X as well as protein C and protein S and the effect of warfarin on kinetic rates.
- Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban-an oral, direct Factor Xa inhibitor.
- Burghaus R, Coboeken K, Gaub T, Niederalt C, Sensse A, Siegmund HU, Weiss W, Mueck W, Tanigawa T, Lippert J
- Frontiers in physiology , 1/ 2014 , Volume 5 , pages: 417
- Bayer HealthCare Wuppertal, Germany.
- The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy. The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin. Our simulations were based on the recommended anticoagulant dosing regimen for stroke prevention in patients with atrial fibrillation. The effects of the combination of discontinued warfarin plus rivaroxaban were simulated using an extended version of a previously validated blood coagulation computer model. A strong synergistic effect of the two distinct mechanisms of action was observed in the first 2-3 days after warfarin discontinuation; thereafter, the effect was close to additive. Nomograms for the introduction of rivaroxaban therapy after warfarin discontinuation were derived for Caucasian and Japanese patients using safety and efficacy criteria described previously, together with the coagulation model. The findings of our study provide a mechanistic pharmacologic rationale for dosing schedules during the therapy switch from warfarin to rivaroxaban and support the switching strategies as outlined in the Summary of Product Characteristics and Prescribing Information for rivaroxaban.
|Burghaus2014.xml||SBML L2V4 representation of Burghaus2014 - Simulating blood coagulation factor Xa inhibitors||37.70 KB||Preview | Download|
|fig2_2.png||Simulation behaviour with non-zero Warfarin concentration.||20.07 KB||Preview | Download|
|fig2_1.png||Simulation behaviour once Warfarin concentration was set to zero.||23.04 KB||Preview | Download|
|Burghaus2014.cps||Model COPASI file. Attempt at reproducing figure 2. Simulated behaviour for 'Onset of Therapy' and 'Discontinuation of therapy' was completely opposite to what is presented in the publication. Species' levels rose when warfarin concentration was non-zero and levels decreased when warfarin levels were set to zero.||83.21 KB||Preview | Download|