Abstract

Introduction: Rivaroxaban is an oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Two large, phase IIb, dose-finding studies investigating rivaroxaban for the treatment of acute, proximal DVT, showed that rivaroxaban once daily (od) and twice daily (bid) had similar efficacy and safety profiles to standard therapy. In order to characterize the population PK/PD of rivaroxaban for DVT treatment, a population model was developed based on data from healthy subjects.

Methods: Sparse PK/PD samples from 870 patients across the two studies were analyzed using non-linear, mixed-effect population modeling (NONMEM), version V level 1.1. The program analyzed population data to give estimates of mean values and variability in the population. Prothrombin time (PT) was determined at a central laboratory and was used in the PD investigation. For the PK profile, data was pooled from both clinical trials and specific exposure parameters for rivaroxaban, such as area under the plasma concentration-time curve (AUC), maximum and minimum plasma concentrations (Cmax and Ctrough, respectively) were predicted for each patient according to the dosing regimen received.

Results: The PK of rivaroxaban were well described by an oral, one-compartment model, with demographic factors influencing clearance (age, renal function) and volume of distribution (age, body weight, gender); variations due to these factors were moderate, suggesting fixed dosing may be possible. Co-medications (e.g. diuretics, NSAIDs, aspirin) had no relevant effects on the PK of rivaroxaban. Rivaroxaban Cmax and Ctrough concentrations increased dose dependently (Table). As expected, Cmax was higher and Ctrough was lower after od dosing compared with bid dosing, at equivalent total daily doses; however, 90% confidence intervals overlapped, suggesting that od dosing with rivaroxaban should not expose patients to a greater risk of bleeding (at Cmax) or VTE (at Ctrough) than bid dosing. Clinically relevant rivaroxaban plasma concentrations correlated linearly with PT, confirming that it would be suitable for measuring rivaroxaban exposure, if necessary.

Conclusions: The PK and PD of rivaroxaban were predictable with od and bid dosing, and affected by expected demographic factors in patients receiving it for DVT treatment. Combined with efficacy and safety results, this analysis aided the selection of an initial, intensified bid regimen followed by convenient, long-term rivaroxaban 20 mg od, for investigation in phase III studies in this indication.

Predicted rivaroxaban PK parameters

ParameterRivaroxaban total daily dose
*Values are shown as means (90% confidence intervals) 
 20 mg 30 mg 40 mg 60 mg 
n (od/bid) 134/117 134/- 252/114 -/119 
od Cmax (μg/L)* 270.6 (189.1–418.7) 324.6 (234.2–491.3) 406.5 (268.4–599.9) 
bid Cmax (μg/L)* 211.5 (130.3–360.7) 320.9 (209.9–517.9) 400.6 (244.2–749.5) 
od Ctrough (μg/L)* 25.5 (5.9–86.9) 33.8 (8.4–132.9) 42.3 (9.7–161.8) 
bid Ctrough (μg/L)* 65.1 (17.2–193.6) 104.2 (31.3–277.8) 143.1 (46.6–347.9) 
ParameterRivaroxaban total daily dose
*Values are shown as means (90% confidence intervals) 
 20 mg 30 mg 40 mg 60 mg 
n (od/bid) 134/117 134/- 252/114 -/119 
od Cmax (μg/L)* 270.6 (189.1–418.7) 324.6 (234.2–491.3) 406.5 (268.4–599.9) 
bid Cmax (μg/L)* 211.5 (130.3–360.7) 320.9 (209.9–517.9) 400.6 (244.2–749.5) 
od Ctrough (μg/L)* 25.5 (5.9–86.9) 33.8 (8.4–132.9) 42.3 (9.7–161.8) 
bid Ctrough (μg/L)* 65.1 (17.2–193.6) 104.2 (31.3–277.8) 143.1 (46.6–347.9) 

Author notes

Disclosure:Employment: Wolfgang Mueck: Bayer HealthCare AG. Research Funding: Giancarlo Agnelli, Harry Buller: Bayer HealthCare.