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. 2015 Jun;79(6):959-66.
doi: 10.1111/bcp.12571.

Contribution of Rivaroxaban to the International Normalized Ratio When Switching to Warfarin for Anticoagulation as Determined by Simulation Studies

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Free PMC article

Contribution of Rivaroxaban to the International Normalized Ratio When Switching to Warfarin for Anticoagulation as Determined by Simulation Studies

Hans-Ulrich Siegmund et al. Br J Clin Pharmacol. .
Free PMC article

Abstract

Aim: This study evaluated the influence of rivaroxaban 20 mg once daily on international normalized ratio (INR) during the co-administration period when switching from rivaroxaban to warfarin.

Methods: We developed a calibrated coagulation model that was qualified with phase I clinical data. Prothrombin time and INR values were simulated by use of phospholipid concentrations that matched Neoplastin Plus® and Innovin® reagents. To simulate the combined effects of rivaroxaban and warfarin on INR during switching, warfarin initiation was simulated by adjusting the magnitude of the warfarin effect to reach the desired target INRs over the course of 21 days. The warfarin effect values (obtained every 6 h) and the desired rivaroxaban plasma concentrations were used. Nomograms were generated from rivaroxaban induced increases in INR.

Results: The simulation had good prediction quality. Rivaroxaban induced increases in the total INR from the warfarin attributed INR were seen, which increased with rivaroxaban plasma concentration. When the warfarin only INR was 2.0-3.0, the INR contribution of rivaroxaban with Neoplastin Plus® was 0.5-1.2, decreasing to 0.3-0.6 with Innovin® at median trough rivaroxaban plasma concentrations (38 μg l(-1) ).

Conclusions: The data indicate that measuring warfarin induced changes in INR are best performed at trough rivaroxaban concentrations (24 h after rivaroxaban dosing) during the co-administration period when switching from rivaroxaban to warfarin. Furthermore, Innovin® is preferable to Neoplastin Plus® because of its substantially lower sensitivity to rivaroxaban, thereby reducing the influence of rivaroxaban on the measured INR.

Keywords: international normalized ratio; prothrombin time; rivaroxaban; simulation; switch of medication; warfarin.

Figures

Figure 1
Figure 1
Simulated prothrombin time test results (dots) compared with actual coagulation test values (line) over a clinically relevant rivaroxaban concentration range to qualify simulated international normalized ratio (INR) changes in the presence of rivaroxaban in the current model
Figure 2
Figure 2
A typical example of a warfarin equilibration simulation over a 21 day period, reaching a target international normalized ratio (INR) of 2.5. (A) R-warfarin and S-warfarin (top and bottom lines) pharmacokinetics are displayed in arbitrary units. formula image, R-warfarin; formula image, S-warfarin. (B) Vitamin K dependent coagulation factors are in fractions of their normal values, all levelling off to their equilibrium value. formula image, II; formula image, VII; formula image, IX; formula image, X; formula image, C; formula image, S. (C) INR (solid green line) reaches the target (broken line), defined as before the next warfarin dose. formula image, INR; formula image, target
Figure 3
Figure 3
Combined rivaroxaban and warfarin induced international normalized ratio (INR) simulation (emulating Neoplastin Plus®) vs. corresponding warfarin only INR simulation. Data shown are 5th percentile (3 μg ml−1), median (38 μg ml−1) and 95th percentile (160 μg ml−1) for 24 h after a 20 mg rivaroxaban dose (rivaroxaban trough). Circles represent differences in mean INR values from a phase I study of transitioning from steady-state warfarin to rivaroxaban (vs. transitioning from steady-state warfarin to placebo, or rivaroxaban only without pre-treatment with warfarin) . INR range is reduced to match the INR range observed in the phase I study. formula image, 3 μg ml−1; formula image, 38 μg ml−1; formula image, 160 μg ml−1
Figure 4
Figure 4
Combined rivaroxaban and warfarin induced international normalized ratio (INR) simulation (emulating Innovin®) vs. corresponding warfarin only INR. Data shown are 5th percentile (3 μg ml−1), median (38 μg ml−1) and 95th percentile (160 μg ml−1) for 24 h after a 20 mg rivaroxaban dose (rivaroxaban trough). formula image, 3 μg ml−1; formula image, 38 μg ml−1; formula image, 160 μg ml−1
Figure 5
Figure 5
Comparison of Neoplastin Plus® and Innovin® reagents. Rivaroxaban induced deviation of international normalized ratio (INR) from warfarin attributed INR vs. warfarin only INR for the median concentration of rivaroxaban at 24 h (38 μg ml−1) after a 20 mg rivaroxaban dose (rivaroxaban trough). formula image, Neoplastin Plus®; formula image, Innovin®

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