Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non‐valvular atrial fibrillation: Results from ROCKET AF

Abstract

Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20 mg for patients with normal/mildly impaired renal function and 15 mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/pharmacodynamic (PD) modeling data from ROCKET AF patients (n ¼ 161) are reported and are used to confirm established rivaroxaban PK and PK/PD models and to re-estimate values of the models' parameters for the current AF population. An oral onecompartment model with first-order absorption adequately described rivaroxaban PK. Age, renal function, and lean body mass influenced the PK model. Prothrombin time and prothrombinase-induced clotting time exhibited a near-linear relationship with rivaroxaban plasma concentration; inhibitory effects were observed through to 24 hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximumeffect (E max ) relationship. Renal function (on prothrombin time; prothrombinase-induced clotting time) and age (on factor Xa activity) had moderate effects on PK/PD models. PK and PK/PD models were shown to be adequate for describing the current dataset. These findings confirm the modeling and empirical results that led to the selection of doses tested against warfarin in ROCKET AF.

Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: A retrospective study

“…We also examined the proportion of patients who had a plasma peak concentration of apixaban, or rivaroxaban below the fifth percentile or plasma peak concentration of dabigatran below the 10th percentile (the lowest percentile reported in the literature for dabigatran);14, 15, 16, 17 the proportion of patients who were switched to warfarin based on the discretion of the treating physician; and the proportion of patients with recurrent VTE and/or stroke during the study follow‐up since the peak concentration was measured. The latter two outcomes were assessed in 22 patients from the anticoagulation clinics.…”

Brain and kidney, victims of atrial microembolism in elderly hospitalized patients? Data from the REPOSI study

“…Rivaroxaban has shown to have a consistent anticoagulant effect and safety in the elderly and in patients with lower GFR [41,44]. In the ROCKET-AF trial, given the available pharmacokinetic data on rivaroxaban in patients with deep vein thrombosis [45], researchers established the safety and efficacy of the drug at a reduced dose (15 mg once daily) in patients with an eGFR of 30-49 mL/min [46,47]. In the Re-LY trial, dabigatran has been analyzed in patients with a CrCl higher than 30 mL/min, in two different dosages (110 mg or 150 mg twice daily), but without a specific dosage for kidney impairment [48].…”

Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients

“…[21][22][23][24][25] A population PK/PD model has been reported for rivaroxaban. 21 In this study, a significant interindividual variability was observed with regard to the baseline value of PT but not the slope for the treatment effect. Therefore, it was possible to extend this model to apixaban and edoxaban by adjusting the slope for the treatment effect based on the prior reports.…”

“…27 In addition, PT increases induced by therapeutic concentrations of FXa inhibitor are small, thus variable compared with warfarin. 21 Therefore, in the present analysis, PT ratio, a relative increase of PT from baseline of each patient, was used for the simulation analyses to avoid these difficulties. The detailed procedure of PT estimation is provided in supplemental Methods.…”

“…PT (or PT international normalized ratio [PT-INR]) is a coagulation test widely used for dose adjustments of warfarin, and the correlations between PT and plasma concentrations of FXa inhibitors have been well analyzed and modeled. 21 In the present study, time-dependent changes of PT in patient populations in each trial were simulated using the published population pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) models [21][22][23][24][25] to analyze their relationships with incidences of ischemic stroke/SE and major bleeding. The constructed models were used to estimate the optimal dose regimens of FXa inhibitors.…”