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

Abstract

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 BackgroundThe anticoagulant actions of the oral direct activated factor Xa inhibitors, rivaroxaban and apixaban, have not previously been directly compared. ObjectivesTo 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. MethodsTwenty‐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. ResultsOverall 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. ConclusionsDespite 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.

Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability

“…This persistently inhibitory effect had been previously shown in subjects analyzed in the absence of TM, but never in the presence. The involvement of the inhibitory dynamic system of activated protein C, formed in the presence of TM by thrombin, contrasts with what occurs in subjects under vitamin K antagonist therapy, whose hypo‐gamma‐carboxylated protein C and protein S are altered .…”

“…While numerous studies on rivaroxaban PK variability have been published, 5–14 few focused on TG parameter time profiles . The originality of the present study lies in two main features: (a) We analyzed ex vivo rivaroxaban PD in a substantial number of healthy volunteers ( n = 59) with TG determined using an automated system under different TF conditions, including one in the presence of TM; (b) relevant PD models were constructed, enabling estimation of interindividual PD variability …”

“…15–22,26–31 However, some persistent issues remain regarding the most appropriate experimental conditions among different methods, including TF concentrations . Moreover, data regarding the magnitude of TG parameter interindividual variability in subjects receiving direct Xa inhibitors are scarce …”

“…13 A more-limited number of studies investigated ex vivo interindividual rivaroxaban PD variability. 9,11,12,[15][16][17][18][19][20][21][22] Among assays measuring clot formation, prothrombin time was the most commonly used in prior published studies, showing a poor suitability to assess rivaroxaban PD, especially at low concentrations. Moreover, prothrombin time sensitivity varies widely across reagents.…”

“…18,23,25 Thrombin generation (TG) has been proposed as an attractive assay to assess in vitro or ex vivo direct FXa inhibitor effect on coagulation based on studies with small series of healthy volunteers or patients, after single or repeated direct Xa inhibitors dose exposure (rivaroxaban, apixaban, edoxaban, or otamixaban). [15][16][17][18][19][20][21][22][26][27][28][29][30][31] However, some persistent issues remain regarding the most appropriate experimental conditions among different methods, including TF concentrations. 32 Moreover, data regarding the magnitude of TG parameter interindividual variability in subjects receiving direct Xa inhibitors are scarce.…”