title: Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban-an oral, direct Factor Xa inhibitor.
abstract: 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.
authors.affiliation: Bayer HealthCare Wuppertal, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Burghaus
authors.affiliation: Bayer Technology Services GmbH Leverkusen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Coboeken
authors.affiliation: Bayer Technology Services GmbH Leverkusen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gaub
authors.affiliation: Bayer Technology Services GmbH Leverkusen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Niederalt
authors.affiliation: Bayer HealthCare Wuppertal, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Sensse
authors.affiliation: Bayer Technology Services GmbH Leverkusen, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Siegmund
authors.affiliation: Bayer Technology Services GmbH Leverkusen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weiss
authors.affiliation: Bayer HealthCare Wuppertal, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueck
authors.affiliation: Bayer HealthCare Wuppertal, Germany.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Tanigawa
authors.affiliation: Bayer HealthCare Wuppertal, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Lippert
keywords: coagulation; combination therapy; mathematical modeling; pharmacodynamics; rivaroxaban; simulation; warfarin