Clinical Pharmacokinetic and Pharmacodynamic Profile of Rivaroxaban

Abstract

Rivaroxaban is an oral, direct Factor Xa inhibitor that targets free and clot-bound Factor Xa and Factor Xa in the prothrombinase complex. It is absorbed rapidly, with maximum plasma concentrations being reached 2–4 h after tablet intake. Oral bioavailability is high (80–100 %) for the 10 mg tablet irrespective of food intake and for the 15 mg and 20 mg tablets when taken with food. Variability in the pharmacokinetic parameters is moderate (coefficient of variation 30–40 %). The pharmacokinetic profile of rivaroxaban is consistent in healthy subjects and across a broad range of different patient populations studied. Elimination of rivaroxaban from plasma occurs with a terminal half-life of 5–9 h in healthy young subjects and 11–13 h in elderly subjects. Rivaroxaban produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for inhibition of Factor Xa activity can be described by an Emax model, and prothrombin time prolongation by a linear model. Rivaroxaban does not inhibit cytochrome P450 enzymes or known drug transporter systems and, because rivaroxaban has multiple elimination pathways, it has no clinically relevant interactions with most commonly prescribed medications. Rivaroxaban has been approved for clinical use in several thromboembolic disorders.

Major Bleeding Complications and Persistence With Oral Anticoagulation in Non‐Valvular Atrial Fibrillation: Contemporary Findings in Real‐Life Danish Patients

“…Notably, findings from our landmark analyses suggest that warfarin users initially had very good persistence, but when looking beyond the first 90 days, we found, from the cumulative incidence and the adjusted Cox model, higher persistence for apixaban and rivaroxaban and lower for dabigatran and warfarin. The fact that gastrointestinal side effects have frequently been reported in dabigatran users could potentially be a mechanism behind our finding that dabigatran users were more likely to be nonpersistent compared with apixaban users 19, 24. Several compliance studies have shown that persistence to treatment is strongly affected by the number of tablets taken daily 25.…”

Pharmacological profile of non-vitamin K antagonist oral anticoagulants

“…After multiple doses, there was no significant accumulation of the drug (Mueck et al, 2014;Kubitza et al, 2005). There are no significant differences in maximal inhibition of factor Xa activity between the first and second daily doses (Kubitza et al, 2005).…”

“…This active substance presents low solubility pH-independent in water and high permeability (EMA, 2016;Mueck et al, 2014).…”

“…Its oral absorption is almost complete and oral bioavailability is high (80-100%). Under fasting conditions, its bioavailability is 66% (EMA, 2016;Mueck et al, 2014). Intake with food and types of food (high-fat or high-carbohydrate meal) does not affect the plasma concentrations of Rivaroxaban (doses of 2.5 and 10 mg), that is, area under the plasma concentrationtime curve.…”

“…Intake with food and types of food (high-fat or high-carbohydrate meal) does not affect the plasma concentrations of Rivaroxaban (doses of 2.5 and 10 mg), that is, area under the plasma concentrationtime curve. However, there is 39% increase in its plasma concentration when rivaroxaban 20 mg tablets are taken together with food (EMA, 2016;Mueck et al, 2014). Its half-lives are 5 to 9 h in young, healthy subjects and 11 to 13 hours in elderly subjects (EMA, 2016).…”