No interaction between rivaroxaban – a novel, oral, direct Factor Xa inhibitor – and atorvastatin Dagmar Kubitza1, Wolfgang Mueck1, Michael Becka21Clinical Pharmacology, 2Department of Biometry, Pharmacometry, Bayer HealthCare AG, Wuppertal, GermanyIntroduction Rivaroxaban is an oral, once-daily, direct Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders,1 including stroke prevention in patients with atrial fibrillation and secondary prevention of cardiovascular events in patients with acute coronary syndrome2,3 Atorvastatin is a synthetic lipid-lowering drug used to treat hypercholesterolaemia and prevent cardiovascular disease. It is currently being investigated for the prevention of atrial fibrillation following cardiothoracic surgery4,5
◆ Future therapy involving the co-administration of rivaroxaban and Figure 2. Plasma concentration–time profile of (A) single-dose rivaroxaban 20 mg with and without steady-state atorvastatin in healthy male subjects, and (B) steady-state atorvastatin atorvastatin is likely in patients with cardiovascular diseases
following administration of steady-state atorvastatin with and without single-dose rivaroxaban20 mg (geometric means; n=19).
◆ Rivaroxaban did not affect the PK of steady-state atorvastatin and atorvastatin-
lactone or its cytochrome P450 3A4-mediated metabolite 2-hydroxy-atorvastatin(Figure 2B; Table 2)
◆ To investigate the effect of steady-state atorvastatin on the safety, pharmacokinetics
Table 2. Effect of single-dose rivaroxaban 20 mg on the pharmacokinetic parameters of
(PK) and pharmacodynamics (PD) of rivaroxaban. In addition, the effect of
atorvastatin and atorvastatin-lactone, and its cytochrome P450 3A4-mediated metabolite
rivaroxaban on the PK of atorvastatin was also assessed
2-hydroxy-atorvastatin in healthy males. Data are geometric means (geometric coefficient ofvariation) unless otherwise indicated
Parameter Atorvastatin Atorvastatin LS-means ratio + rivaroxaban rivaroxaban + atorvastatin vs atorvastatin Study design alone (90% CI)
◆ In this three-way crossover study, healthy male subjects were randomized to receive
rivaroxaban 20 mg alone (day 1 in group A), atorvastatin alone to steady state
(10 mg once daily on days 1–3 and 20 mg once daily on days 4–7 in group B), and
the combination of both, with rivaroxaban administered on day 7 (group C; Figure 1).
There was a washout period of approximately 2 weeks between each study arm
AUC, µg⋅h/l Pharmacokinetic assessments
◆ The pharmacokinetic profiles of single-dose rivaroxaban alone (day 1, group A) and in
the presence of steady-state atorvastatin (day 7, group C) were determined (Figure 1)
AUC, area under the plasma concentration–time curve; CI, confidence interval; C
, time to reach maximum drug concentrations; t terminal half-life. aMedian
(range). bArithmetic mean (standard deviation).
◆ The amount of unchanged rivaroxaban excreted in the urine was similar when
rivaroxaban was administered alone (33.4%) and with steady-state atorvastatin
◆ Rivaroxaban alone inhibited FXa activity by a maximum of 56% and prolonged PT
◆ Atorvastatin alone did not affect FXa activity or PT
◆ Steady-state atorvastatin did not affect rivaroxaban-mediated inhibition of FXa
activity and prolongation of PT (Figure 3)
(single-dose rivaroxaban + steady-state atorvastatin)
od, once daily dose; PK, pharmacokinetic analysis; PD, pharmacodynamic analysis. Figure 1. Three-way crossover study design.
The pharmacokinetic profiles of steady-state atorvastatin alone (day 7, group B) and
the effects of single-dose rivaroxaban on the PK of atorvastatin (acid and lactone
forms), and its cytochrome P450 3A4-mediated metabolite 2-hydroxy-atorvastatin
Serial blood samples were collected on days 1–4 in group A; and on days 7–10 in
◆ The pharmacodynamic effects of single-dose rivaroxaban alone (day 1, group A) and
the effects of steady-state atorvastatin on the PD of single-dose rivaroxaban weredetermined (day 7, group C)
Figure 3. Effect of single-dose rivaroxaban 20 mg alone, steady-state atorvastatin alone, and
◆ Inhibition of FXa activity and prolongation of prothrombin time (PT) were
single-dose rivaroxaban in combination with steady-state atorvastatin on (A) inhibition of
Factor Xa activity, and (B) prolongation of prothrombin time in healthy male subjects (medianvalues; n=19). Safety and tolerability
◆ Rivaroxaban was well tolerated alone and in combination with steady-state
atorvastatin. There was no evidence of relevant changes in laboratory parameters,vital signs or ECG parameters attributable to rivaroxaban
Pharmacokinetics ◆ Steady-state atorvastatin did not affect the PK of rivaroxaban (Table 1, Figure 2A) Conclusions Table 1. Effect of steady-state atorvastatin on the pharmacokinetic parameters of single-dose rivaroxaban 20 mg. Data are geometric means (geometric coefficient of variation) unless otherwise indicated
◆ The tolerability, PK and PD of rivaroxaban were not affected by Rivaroxaban Rivaroxaban LS-means ratio co-administration with steady-state atorvastatin + atorvastatin rivaroxaban + atorvastatin vs rivaroxaban alone (90% CI)
◆ The PK of atorvastatin were not affected by co-administration with rivaroxaban
◆ These results suggest that rivaroxaban may be co-administered with atorvastatin in patients with cardiovascular diseases References and disclosures
1. Perzborn E et al. J Thromb Haemost 2005;3:514–521.
4. Lertsburapa K et al. J Thorac Cardiovasc Surg 2008;135:405–411.
2. Singer DE et al. Chest 2004;126:429S–456S.
5. Patti G et al. Circulation 2006;114:1455–1461.
Ae , amount of drug excreted via urine; AUC, area under the plasma concentration–time curve; CI, confidence interval;
3. Harrington RA et al. Chest 2004;126:513S–548S.
6. Kubitza D et al. J Clin Pharmacol 2007;47:218–226.
, maximum drug concentration in plasma; LS-mean, least-square mean; t
maximum drug concentrations; t terminal half-life. aMedian (range). bArithmetic mean (standard deviation).
This study was supported by Bayer HealthCare AG and Scios, Inc. Rivaroxaban is in clinical development and not yet licensed.
Poster P062 presented at the 20th International Congress on Thrombosis (ICT), Athens, Greece; 25–28 June 2008
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