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.

Aims The anticoagulant rivaroxaban is an oral, direct Factor Xa inhibitor for the management of thromboembolic disorders. Metabolism and excretion involve cytochrome P450 3A4 (CYP3A4) and 2J2 (CYP2J2), CYP‐independent mechanisms, and P‐glycoprotein (P‐gp) and breast cancer resistance protein (Bcrp) (ABCG2). Methods The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P‐gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers. Results Rivaroxaban did not interact with midazolam (CYP3A4 probe substrate). Exposure to rivaroxaban when co‐administered with midazolam was slightly decreased by 11% (95% confidence interval [CI] −28%, 7%) compared with rivaroxaban alone. The following drugs moderately affected rivaroxaban exposure, but not to a clinically relevant extent: erythromycin (moderate CYP3A4/P‐gp inhibitor; 34% increase [95% CI 23%, 46%]), clarithromycin (strong CYP3A4/moderate P‐gp inhibitor; 54% increase [95% CI 44%, 64%]) and fluconazole (moderate CYP3A4, possible Bcrp [ABCG2] inhibitor; 42% increase [95% CI 29%, 56%]). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4, P‐gp/Bcrp (ABCG2) inhibitors (and potential CYP2J2 inhibitors) ketoconazole (158% increase [95% CI 136%, 182%] for a 400 mg once daily dose) and ritonavir (153% increase [95% CI 134%, 174%]). Conclusions Results suggest that rivaroxaban may be co‐administered with CYP3A4 and/or P‐gp substrates/moderate inhibitors, but not with strong combined CYP3A4, P‐gp and Bcrp (ABCG2) inhibitors (mainly comprising azole‐antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi‐pathway inhibitors of rivaroxaban clearance and elimination.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Prior to the commencement of this study, it was already known that rivaroxaban is partially cleared via the kidneys and an influence of renal insufficiency on rivaroxaban pharmacokinetics and exposure was anticipated. WHAT THIS STUDY ADDS• As many patients in the target indications of rivaroxaban will be elderly, a precise quantitative knowledge of the influence of renal function on rivaroxaban pharmacokinetics and exposure is mandatory for adequate labelling recommendations (in the context of benefit/risk provided by phase III studies) to guide therapy. This study provided detailed insight on both rivaroxaban pharmacokinetics and pharmacodynamic behaviour in renal impairment including severely renally impaired subjects. AIMThis study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10 mg single dose), an oral, direct Factor Xa inhibitor. METHODSSubjects (n = 32) were stratified based on measured creatinine clearance: healthy controls (Ն80 ml min -1 ), mild (50-79 ml min -1 ), moderate (30-49 ml min -1 ) and severe impairment (<30 ml min -1 ). RESULTSRenal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration-time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively. CONCLUSIONSRivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.

This population analysis in patients undergoing major orthopaedic surgery demonstrated that rivaroxaban has predictable, dose-dependent pharmacokinetics that were well described by an oral one-compartment model and affected by expected covariates. Rivaroxaban exposure could be assessed using the prothrombin time, if necessary, but not the international normalized ratio. The findings suggested that fixed dosing of rivaroxaban may be possible in patients undergoing major orthopaedic surgery.

ABSTRACT:Rivaroxaban is a novel, oral, direct factor Xa inhibitor for the prevention and treatment of thromboembolic disorders. The objective of this study was to investigate the in vivo metabolism and excretion of rivaroxaban in rats, dogs, and humans. Single doses of [ 14 C]rivaroxaban (3 and 1 mg/kg) were administered to rats (orally/ intravenously) and dogs (orally), respectively. A single oral dose of [ 14 C]rivaroxaban (10 mg) was administered to healthy human males (n ‫؍‬ 4). Plasma and excreta were collected and profiled for radioactivity. Recovery of total radioactivity was high and >92% in all species. Unchanged rivaroxaban was the major compound in plasma at all time points investigated, across all species. No major or pharmacologically active circulating metabolites were detected. Rivaroxaban and its metabolites were rapidly excreted; urinary excretion of radioactivity was 25 and 52%, and fecal excretion was 67 and 43% of the dose in rats and dogs, respectively. In humans, 66% of the dose was excreted renally (36% unchanged drug) and 28% in the feces. Radioactivity profiles in excreta were similar across species. Three metabolic pathways were identified: oxidative degradation of the morpholinone moiety (major pathway) and hydrolysis of the central amide bond and of the lactam amide bond in the morpholinone ring (minor pathways). M-1, the main metabolite in excreta of all species, was eliminated via both renal and fecal/biliary routes. In total, 82 to 89% of the dose administered was assigned to unchanged rivaroxaban and its metabolites in the excreta of rats, dogs, and humans.Rivaroxaban is a novel, oral, direct factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. More recently, it has received approval in Canada and the European Union for use in the prevention of venous thromboembolism in patients undergoing elective total hip or knee replacement surgery. Rivaroxaban is a selective inhibitor not only of free FXa (K i 0.4 nM), but also of prothrombinase activity and fibrinassociated FXa activity Perzborn et al., 2005). In vitro, rivaroxaban was shown to inhibit thrombin generation and prolong clotting times Perzborn et al., 2005) and, in vivo, it had potent antithrombotic effects in a variety of animal venous and arterial thrombosis models Biemond et al., 2007).Pharmacokinetic (PK) studies of rivaroxaban in rats and dogs have been reported previously (Weinz et al., 2005). These studies demonstrated that rivaroxaban was absorbed rapidly after oral dosing (absolute bioavailability 57-66 and 60 -86% in rats and dogs, respectively), had a favorable PK profile with dose proportional increases in area under the concentration-time curve (AUC) and was rapidly excreted via renal and fecal/biliary routes. Rivaroxaban has also been shown to demonstrate dose-proportional pharmacokinetics and predictable pharmacodynamics in single (up to 80 mg)-and multipledose studies in healthy subjects and patients with no evidence of accumulation (Kubitza et ...

Anticoagulants are often dose adjusted, or their use restricted, in patients with extremes of body weight. Rivaroxaban (BAY 59-7939) is a novel, oral, direct factor Xa inhibitor in clinical development. This was a randomized, single-blind, placebo-controlled, parallel-group study in healthy male and female subjects to assess the effect of extreme body weight (< or = 50 kg and >120 kg), and gender, on the safety, tolerability, pharmacokinetics, and pharmacodynamics of rivaroxaban 10 mg, compared with subjects of normal weight (70-80 kg). Rivaroxaban was well tolerated. Cmax of rivaroxaban was unaffected in subjects >120 kg but was increased by 24% in subjects weighing < or = 50 kg, resulting in a small (15%) increase in prolongation of prothrombin time, which was not considered clinically relevant. The area under the curve was unaffected by body weight or gender. No other clinically relevant differences were observed, suggesting that rivaroxaban is unlikely to require dose adjustment for body weight or gender.

To investigate the influence of food and administration of an antacid (aluminum-magnesium hydroxide) or ranitidine on the absorption of BAY 59-7939 (rivaroxaban), 4 randomized studies were performed in healthy male subjects. In 2 food interaction studies, subjects received BAY 59-7939, either as two 5-mg tablets (fasted and fed), four 5-mg tablets (fasted), or one 20-mg tablet (fasted and fed). In 2 drug interaction studies, BAY 59-7939 (six 5-mg tablets) was given alone or with ranitidine (150 mg twice daily, preceded by a 3-day pretreatment phase) or antacid (10 mL). Plasma samples were obtained to assess pharmacokinetic and pharmacodynamic parameters of BAY 59-7939. In the presence of food, time to maximum concentration (t(max)) was delayed by 1.25 hours; maximum concentration (C(max)) and area under the curve (AUC) were increased, with reduced interindividual variability at higher doses of BAY 59-7939. Compared with baseline, BAY 59-7939 resulted in a relative increase in maximum prothrombin time (PT) prolongation of 44% (10 mg) and 53% (20 mg) in the fasted state, compared with 53% and 83% after food. Time to maximum PT prolongation was delayed by 0.5 to 1.5 hours after food, with no relevant influence of food type. No significant difference in C(max) and AUC was observed with coadministration of BAY 59-7939 and ranitidine or antacid.

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