Rivaroxaban Precision Dosing Strategy for Real‐World Atrial Fibrillation Patients

Figures

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  Figure 1. Current rivaroxaban dosing recommendations are predicted to yield clinically significant deviations in the average 24‐hour steady‐state area under the plasma concentration‐vs.‐time curve (AUC) for patients outside a certain range of creatinine clearance (CrCl). The solid gray horizontal line demarcates where the predicted AUC is equal to 3,325.6 μg/h per liter. The dotted gray reference lines represent a 20% increase and 20% decrease in AUC from 3,325.6 μg/h per liter. The predicted AUC vs. CrCl from 15 ml/min to 250 ml/min for virtual 73‐kg, 73‐year‐old male subjects is displayed. The solid black line represents the recommended dose of 20 mg once daily for patients with CrCl >50 ml/min. The dashed black line represents the recommended dose of 15 mg once daily for patients with CrCl between 15 and 50 ml/min. The predicted AUC exceeds the ±20% threshold from target AUC when CrCl is <26 ml/min or >117 ml/min.

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  Figure 2. The proposed precision dosing strategies are predicted to result in rivaroxaban average 24‐hour steady‐state area under the plasma concentration‐vs.‐time curve (AUC) values within ±20% of the target AUC for physiologically relevant ranges of creatinine clearance (CrCl) (15–250 ml/min) in adults. The target AUC (3,325.6 μg/h per liter) is represented by the solid gray horizontal line. The ±20% thresholds from the target AUC are demarcated by the dotted gray horizontal lines. The predicted AUC according to CrCl is displayed for the CrCl‐based dosing strategy. Predictions are for a 73‐kg, 73‐year‐old male subject.

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  Figure 3. (a) Average predicted pharmacokinetic profiles for atrial fibrillation patients with creatinine clearance (CrCl) between 15 and 250 ml/min have significant differences when current rivaroxaban dose recommendations are used. (b) Proposed CrCl‐based precision dosing strategy is predicted to yield comparable exposure across the broad range of physiologically relevant CrCl values while reducing large fluctuations in peak and trough concentrations. All plasma concentration‐vs.‐time profiles were predicted for a 73‐kg, 73‐year‐old male virtual patient according to various levels of renal function. Line color corresponds to CrCl and is consistent across panels (a) and (b). BID, twice daily; CrCl, creatinine clearance; QD, once daily.