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Ict 2008 atorvastatin interactionNo interaction between rivaroxaban
– a novel, oral, direct Factor Xa inhibitor – and atorvastatin
Dagmar Kubitza1, Wolfgang Mueck1, Michael Becka2 1Clinical Pharmacology, 2Department of Biometry, Pharmacometry, Bayer HealthCare AG, Wuppertal, Germany Introduction
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
◆ 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- Objective
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
alone (90% CI)
◆ In this three-way crossover study, healthy male subjects were randomized to receive AUC, µg⋅h/l
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
◆ 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, µg⋅h/l
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 Pharmacodynamics
◆ 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 Pharmacodynamic assessments
◆ 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)
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
◆ The tolerability, PK and PD of rivaroxaban were not affected by
co-administration with steady-state atorvastatin
rivaroxaban + atorvastatin
vs rivaroxaban alone (90% CI)
◆ The PK of atorvastatin were not affected by co-administration with
◆ 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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