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

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

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

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

Concentration-effect: RE-LY

Concentration-safety: RE-LY

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

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

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.

Results apixaban

weaker but still highly significant y = 2.321 + 0.944x 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 = 6.114 + 0.827x 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)

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 (16 - 66)

Trough rivaroxaban concentration by LC/MS-MS y=-1.668+0.85x 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=2.170+0.64x 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

Apixaban summary Plasma concentration varied 12-fold overall. The median trough apixaban plasma concentration measured by LC-MS/MS was 75 ng/ml (range 15-186 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.

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.

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.

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