Dissociation between the pharmacokinetics and pharmacodynamics of once‐daily rivaroxaban and twice‐daily apixaban: a randomized crossover study

• Published in: Journal of thrombosis and haemostasis 2017-10, Vol.15 (10), p.2017-2028
• Main Authors: Kreutz, R., Persson, P. B., Kubitza, D., Thelen, K., Heitmeier, S., Schwers, S., Becka, M., Hemmrich, M.
• Format: Article
• Language: English
• Subjects: activated partial thromboplastin time; Adult; Anticoagulants; apixaban; Blood Coagulation - drug effects; Cross-Over Studies; direct factor Xa inhibitors; Drug Administration Schedule; Factor Xa Inhibitors - administration & dosage; Factor Xa Inhibitors - adverse effects; Factor Xa Inhibitors - blood; Factor Xa Inhibitors - pharmacokinetics; Fibrillation; Germany; Healthy Volunteers; Humans; Male; Middle Aged; Partial Thromboplastin Time; Pharmacodynamics; Pharmacokinetics; Predictive Value of Tests; Prothrombin; Prothrombin Time; Pyrazoles - administration & dosage; Pyrazoles - adverse effects; Pyrazoles - blood; Pyrazoles - pharmacokinetics; Pyridones - administration & dosage; Pyridones - adverse effects; Pyridones - blood; Pyridones - pharmacokinetics; Reproducibility of Results; rivaroxaban; Rivaroxaban - administration & dosage; Rivaroxaban - adverse effects; Rivaroxaban - blood; Rivaroxaban - pharmacokinetics; Stroke; Thrombin; Thrombin - metabolism; thrombin generation; Thromboplastin; Young Adult
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.13801

Essentials In this crossover study the anticoagulant effects of rivaroxaban and apixaban were compared. Healthy volunteers received rivaroxaban 20 mg once daily or apixaban 5 mg twice daily. Rivaroxaban was associated with more prolonged inhibition of thrombin generation than apixaban. Rivaroxaban induced a clear prolongation of prothrombin time and activated partial thromboplastin time. Summary Background The anticoagulant actions of the oral direct activated factor Xa inhibitors, rivaroxaban and apixaban, have not previously been directly compared. Objectives To compare directly the steady‐state pharmacokinetics and anticoagulant effects of rivaroxaban and apixaban at doses approved for stroke prevention in patients with non‐valvular atrial fibrillation. Methods Twenty‐four healthy Caucasian male volunteers were included in this open‐label, two‐period crossover, phase 1 study (EudraCT number: 2015‐002612‐32). Volunteers were randomized to receive rivaroxaban 20 mg once daily or apixaban 5 mg twice daily for 7 days, followed by a washout period of at least 7 days before they received the other treatment. Plasma concentrations and anticoagulant effects were measured at steady state and after drug discontinuation. Results Overall exposure was similar for both drugs: the geometric mean area under the plasma concentration–time curve for the 0–24‐h interval was 1830 μg h L−1 for rivaroxaban and 1860 μg h L−1 for apixaban. Rivaroxaban was associated with greater inhibition of endogenous thrombin potential (geometric mean area under the curve relative to baseline during the 0–24‐h interval: 15.5 h versus 17.5 h) and a more pronounced maximal prolongation relative to baseline of prothrombin time (PT) (1.66‐fold versus 1.14‐fold) and activated partial thromboplastin time (APTT) (1.43‐fold versus 1.16‐fold) at steady state than apixaban. Conclusions Despite similar exposure to both drugs, rivaroxaban 20 mg once daily was associated with greater and more sustained inhibition of thrombin generation than apixaban 5 mg twice daily. Sensitive PT and APTT assays can be used to estimate the anticoagulant effects of rivaroxaban.