1. Rivaroxaban and apixaban plasma concentrations at trough in patients with atrial fibrillation
Fadiea Al-Aieshy
PhD-student, MSc Pharm
Department of Medicine Solna, Karolinska Institutet
Clinical Pharmacology, Karolinska University Hospital
Stockholm, Sweden
Conflict of interest: none to declare

2. Direct Oral Anticoagulants (DOAC) Non-Vitamin K Oral Anticoagulants (NOAC)
Direct thrombin inhibitor
- Dabigatran
Direct factor Xa inhibitors
-Rivaroxaban
-Apixaban
-Edoxaban

3. Optimal Safety and Efficacy Dose (concentration) of Anticoagulant
Effect-Safety
Optimal Safety and Efficacy
Thrombosis
Bleeding
Dose (concentration) of Anticoagulant

4. Concentration correlated to effect and safety
Factors affecting concentration
Age
Weight
Compliance
Renal function (particularly dabigatran)
Interactions
Pgp: ex dronedaron, verapamil
CYP3A4 inhibitors/inducers, ex antimycotics, part rivaroxaban, apixaban
PPIs - dabigatran

5. Concentration-effect: RE-LY

6. Concentration-safety: RE-LY

7. Effect – safety : RE-LY Sthlm 10-90e percentil min-max (median 52),
Skeppholm et al., Thromb Res 2014

10. Aims
To show the typical exposure range of apixaban and rivaroxaban in patients with AF
Evaluate different laboratory methods

11. Methods
A total of 141 AF patients treated with either apixaban 2.5 mg/5 mg (n=10/60) twice daily or rivaroxaban 15 mg/20 mg (n=10/61) once daily.
Trough plasma concentrations were measured by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) and Anti-FXa assays calibrated with apixaban/rivaroxaban.

12. Results apixaban

13. weaker but still highly significant
y = x
r2 = 0.96, p<0.001
There were highly significant correlations between directly measured apixaban in plasma and estimated by anti-FXa activity
Anti-Xa Apixaban (ng/mL)
y = x
r2 = 0.78, p<0.001
Anti-Xa Apixaban (ng/mL)
For patients with apixaban concentration by LC-MS/MS ≤ 50 ng/mL the correlation was
weaker but still highly significant
Apixaban by LC-MS/MS (ng/mL)

14. Results rivaroxaban Analytical results All patients n=71 Rivaroxaban
15 mg OD
n=10
20 mg OD
n=61
LC-MS/MS, ng/ml
Median (range) 34
(5 – 84) 30
(22 – 66)
(10th-90th percentile)
13 – 63
22 – 65
13 – 62
Geometric mean 36 38
Anti-FXa, ng/ml 28
(4 - 67) 23
( )

15. Trough rivaroxaban concentration by LC/MS-MS
y= x
r2=0.92, p<0.001
Trough Anti-Xa rivaroxaban (ng/ml)
Median (range)
Trough
(n=71)
LC-MS/MS
ng/mL
34 (5-84)
Anti-FXa assay ng/mL
28 (4-67)
Trough rivaroxaban concentration by LC/MS-MS
y= x
r2=0.79, p<0.001
Trough Anti-Xa rivaroxaban (ng/ml)
Trough rivaroxaban concentration by LC/MS-MS ≤ 30 (ng/ml)
14/10/2015

16. Apixaban summary
Plasma concentration varied 12-fold overall. The median trough apixaban plasma concentration measured by LC-MS/MS was 75 ng/ml (range ng/ml). The typical exposure range (10–90th percentile) observed was roughly between 40 and 120 ng/ml at trough.
Patients receiving the higher dose had significantly higher apixaban concentrations than the low dosed.
Anti-FXa assays correlated strongly with LC-MS/MS but further studies may be needed to evaluate sensitivity and accuracy of the assay in the low plasma concentration range.

17. Rivaroxaban summary
Plasma concentrations varied 17-fold at trough. The median trough rivaroxaban plasma concentration measured by LC-MS/MS was 34 ng/ml (range 5-84 ng/ml).The typical exposure range (10–90th percentile) observed was roughly between 10 and 60 ng/ml at trough.
No significant differences in exposure levels between the high- and low-dose group were found.
Anti-FXa assays correlated strongly with LC-MS/MS, however, at very low concentrations ≤30 ng/ml, the method is less reliable and might underestimate the actual concentrations.

18. Conclusions
Apixaban and rivaroxaban plasma concentrations varied substantially in AF patients. We here describe the range of exposures as well as typical exposure intervals for both drugs. We suggest that these typical exposure intervals may be used for dose guidance.

19. Thank you for your attention