Michael Becka

Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor.

There is a clinical need for new oral anticoagulants to prevent and treat thromboembolic diseases. Given its integral role in the coagulation cascade, factor Xa is a particularly promising target for new anticoagulation therapies. The aim of this study was to investigate the safety, pharmacodynamics, and pharmacokinetics of BAY 59–7939, an oral, direct factor Xa inhibitor.

Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects

ABSTRACT Objective: The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of rivaroxaban – a novel, oral, direct Factor Xa (FXa) inhibitor – in healthy elderly subjects. Research design and methods: In this single-centre, single-blind, placebo-controlled, parallel-group, dose-escalation study, 48 subjects (aged 60–76 years) were randomized to receive a single oral dose of 30, 40 or 50 mg of rivaroxaban or placebo. Results: Rivaroxaban was absorbed rapidly, reaching peak plasma concentration (Cmax) 4 h after dosing in all groups. Bioavailability, in terms of the area under the plasma concentration–time curve (AUC) and Cmax, increased slightly (less than dose proportionally) after administration of rivaroxaban 40 mg compared with 30 mg, but was not increased further with rivaroxaban 50 mg. Rivaroxaban pharmacodynamic effects (inhibition of FXa activity and prolongation of prothrombin time, activated partial thromboplastin time and HepTest) all showed a similar pattern, with maximum inhibition of FXa activity increasing from 68% after rivaroxaban 30 mg to 75% after 40 mg and no further increase with the 50 mg dose. Most adverse events were mild; observed rates were less than placebo for the 30 and 40 mg dose groups, and similar to placebo for 50 mg. No differences were found between male and female subjects. Effects of rivaroxaban doses above 50 mg were not investigated in this study. Conclusions: Each single dose of rivaroxaban was well tolerated, with predictable pharmacokinetics and pharmacodynamics at doses up to 40 mg, and provided effective anticoagulation in healthy elderly subjects. Adverse events were somewhat elevated in the 50 mg group, but given the small sample size, no specific conclusions can be drawn about this dosing level.

Effect of Food, an Antacid, and the H2 Antagonist Ranitidine on the Absorption of BAY 59–7939 (Rivaroxaban), an Oral, Direct Factor Xa Inhibitor, in Healthy Subjects

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 (tmax) was delayed by 1.25 hours; maximum concentration (Cmax) 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 Cmax and AUC was observed with coadministration of BAY 59–7939 and ranitidine or antacid.

Body Weight Has Limited Influence on the Safety, Tolerability, Pharmacokinetics, or Pharmacodynamics of Rivaroxaban (BAY 59‐7939) in Healthy Subjects

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 (≤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 ≤5 0 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.

Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban-an oral, direct factor Xa inhibitor : Are not affected by aspirin

Rivaroxaban (BAY 59‐7939) is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. This was a randomized, 2‐way crossover study in healthy male subjects, with an aspirin run‐in period, to examine whether aspirin influences the safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban. All treatments were well tolerated; drug‐related adverse events were mild and transient. Aspirin did not alter the effects of rivaroxaban on Factor Xa activity or clotting tests. Platelet aggregation and bleeding time were not affected by rivaroxaban, and rivaroxaban did not influence the effects of aspirin on these parameters to a clinically relevant extent. Aspirin did not affect the pharmacokinetics of rivaroxaban, including the fraction unbound. This study suggests that there is no clinically relevant interaction between rivaroxaban and aspirin and that the 2 drugs could be administered concomitantly at the doses used in this study.

Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct Factor Xa inhibitor - in healthy subjects

OBJECTIVE Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa (FXa) inhibitor being developed for the prevention and treatment of thromboembolic disorders. This analysis aimed to define population models for the pharmacokinetics (PK) and pharmacodynamics (PD) ofrivaroxaban in healthy males. METHODS Non-linear, mixed-effect modeling was used to analyze rivaroxaban plasma concentration and PD data (FXa activity and clotting tests) from subjects in a phase I, multiple-ascending-dose study. Subjects received 5 mg rivaroxaban once, twice or three times daily, or 10, 20 or 30 mg rivaroxaban twice daily. RESULTS The population PK of rivaroxaban were well described by an oral, two-compartment model with first-order absorption and elimination from the central compartment. Population mean estimates for apparent oral clearance and volume of distribution for the central compartment were 9.2 1/h and 55 1, respectively, with moderate inter-individual variability (17.4% and 30.7%, respectively). Total volume of distribution for rivaroxaban at steady state was approximately 70 1. Residual (unexplained) variability was 25%. FXa activity correlated with rivaroxaban plasma concentrations following an inhibitory Emax model; prothrombin time (PT) and rivaroxaban plasma concentrations correlated with a linear model, with a slope of 4.6 s/(100 microg/1). Inter-individual variability was low for the correlation with PT. The models derived were used to define sampling windows for population PK/PD modeling in Phase II studies. CONCLUSIONS This analysis confirms that rivaroxaban has predictable, dose-proportional PK and PD. The linear correlation between rivaroxaban plasma concentrations and PT suggests that this test might be useful to assess rivaroxaban exposure in patients, if required.

Effects of the Oral, Direct Factor Xa Inhibitor Rivaroxaban on Platelet‐Induced Thrombin Generation and Prothrombinase Activity1

Rivaroxaban (BAY 59‐7939) is an oral, direct factor Xa inhibitor in advanced development. This study was undertaken to investigate its effects on thrombin generation. In this placebo‐controlled, randomized, crossover study, 12 healthy subjects received rivaroxaban (single 5‐ or 30‐mg dose) or placebo. Thrombin generation was investigated by measuring the endogenous thrombin potential and prothrombinase‐induced clotting time. Maximal effect of rivaroxaban was observed 2 hours after drug administration: prothrombinase‐induced clotting time was prolonged 1.8 and 2.3 times baseline after rivaroxaban 5 and 30 mg, respectively. Collagen‐induced endogenous thrombin potential was reduced by ∼80% and ∼90% compared with baseline after rivaroxaban 5 and 30 mg, respectively, and tissue factor‐induced endogenous thrombin potential was reduced by ∼40% (5 mg) and ∼65% (30 mg), respectively. Thrombin generation remained inhibited for 24 hours. There was a close correlation between plasma concentration of rivaroxaban and prolongation of prothrombinase‐induced clotting time and reduction in endogenous thrombin potential. Rivaroxaban strongly inhibits platelet‐induced thrombin generation, after activation of either platelets or the coagulation pathway, even in the presence of minimal factor Xa inhibition in plasma.

The effect of food on the absorption and pharmacokinetics of rivaroxaban

OBJECTIVE Doses of 10 mg, 15 mg, and 20 mg of rivaroxaban are approved for the treatment and prevention of thromboembolic disorders in adult patients. In six Phase I studies, the pharmacokinetics, safety, and tolerability of 2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg rivaroxaban were investigated in healthy male subjects, and the influence of food on these parameters was investigated for the 10 mg, 15 mg, and 20 mg tablet doses. In addition, an oral suspension containing 1 mg/ml rivaroxaban, which is under investigation for future use in the pediatric population, was investigated at doses of 10 mg and 20 mg. MATERIALS Rivaroxaban was obtained from Bayer Pharma AG, Wuppertal, Germany. METHODS Six independent, single-dose, cross-over studies were performed in healthy male subjects (between 13 and 24 subjects were enrolled in each study) to determine the pharmacokinetics, safety, and tolerability of rivaroxaban under fasting and fed conditions. Study 1 was an absolute bioavailability study that compared 5 mg and 20 mg tablet doses with a 1 mg intravenous solution. Studies 2 and 3 were confirmatory food-effect studies that assessed 10 mg and 20 mg tablet doses, respectively, under fed and fasting conditions. Study 4 was a formulation study that evaluated oral suspensions of 10 mg (fasting) and 20 mg (fasting and fed) rivaroxaban vs. a 10 mg tablet (fasted). Study 5 was a dose-proportionality study that assessed 2.5 mg, 5 mg, and 10 mg tablets under fasting conditions. Study 6 was a dose-proportionality study that assessed tablet doses of 10 mg, 15 mg, and 20 mg under fed conditions. Pharmacokinetic parameters, including the area under the plasma concentration-time curve after a single dose, the maximum drug concentration in plasma after a single dose, dose-adjusted values of area under the plasma concentration-time curve and maximum drug concentration in plasma after a single dose, half-life associated with the terminal slope, and time to maximum concentration in plasma after a single dose were evaluated. Adverse events were classified according to their degree of severity and were summarized using Medical Dictionary for Regulatory Activities preferred terms. RESULTS At all doses, rivaroxaban showed an acceptable safety profile and was well tolerated in healthy individuals. Independent of food and formulation, pharmacokinetic parameters of doses up to 10 mg rivaroxaban were dose proportional and had high oral bioavailability (≥ 80%). Under fasting conditions, pharmacokinetic parameters of 15 mg and 20 mg rivaroxaban increased with dose but were less than dose proportional. However, when taken with food, high bioavailability (≥ 80%) of these doses was achieved independent of formulation. CONCLUSION Pharmacokinetic parameters of doses up to 10 mg rivaroxaban were dose proportional and had high oral bioavailability independent of food or whether administered as tablet or solution. High bioavailability (≥ 80%) of 15 mg and 20 mg rivaroxaban was achieved when taken with food; therefore, these doses need to be taken with food.

The Influence of Age and Gender on the Pharmacokinetics and Pharmacodynamics of Rivaroxaban—An Oral, Direct Factor Xa Inhibitor

A randomized, single‐blind, placebo‐controlled, parallel‐group study was conducted to assess the effect of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban – an oral, direct Factor Xa inhibitor. Subjects (n = 34) were enrolled into four groups: young males or females (aged 18–45 years) and elderly males or females (aged >75 years), and received a single dose of 10 mg rivaroxaban. Pharmacokinetic and pharmacodynamic parameters were determined. Gender had no significant influence on the pharmacokinetics and pharmacodynamics of rivaroxaban. The area under the concentration–time curve (AUC) of rivaroxaban was 41% higher in elderly compared with young subjects; corresponding AUC values for the inhibition of Factor Xa activity and prolongation of prothrombin time were also higher. These changes were the result of reduced rivaroxaban clearance in elderly subjects, mainly owing to decreased renal function. The influence of age was not considered clinically relevant. The maximum plasma concentration was not increased in elderly subjects, and pharmacodynamic parameters returned close to baseline within 24 hours. The results indicate that age alone and gender did not have a clinically relevant effect on the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy subjects after a 10 mg dose.

Randomized, double-blind, crossover study to investigate the effect of rivaroxaban on QT-interval prolongation.

Background: Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. Unwanted pro-arrhythmic effects are a common reason for drugs failing to gain regulatory approval; these properties can be detected by assessing the effect of the drug on the QT interval.Objective: This study was performed, in accordance with International Conference on Harmonisation (ICH) E14 guidance, to assess whether rivaroxaban prolongs the QT interval.Study design: This was a prospective, randomized, double-blind, double-dummy, four-way crossover study.Setting: The study was conducted at a clinical pharmacology research unit.Subjects: Healthy male and female subjects (n = 54) aged ≥50 years were enrolled and remained in the study unit for 3 days for each treatment. Of these, 50 patients were eligible for the QT analysis.Intervention: Subjects received single oral doses of rivaroxaban 45 mg or 15 mg, moxifloxacin 400 mg (positive control), or placebo.Outcome measures: Multiple ECGs were taken at frequent intervals after drug administration, and the QT interval was measured manually under blinded conditions at a central laboratory. The Fridericia correction formula (QTcF) was used to correct the QT interval for heart rate. The primary outcome was the effect of rivaroxaban or moxifloxacin on the placebo-subtracted QTcF 3 hours after administration. The frequency of outlying QTcF values and the tolerability of the treatments were also assessed.Results: All treatments were well tolerated and had no effect on heart rate. Moxifloxacin established the required assay sensitivity; placebo-subtracted QTcF 3 hours after moxifloxacin administration was prolonged by 9.77 ms (95% CI 7.39, 12.15). Placebo-subtracted QTcF values 3 hours after rivaroxaban administration were −0.91 ms (95% CI −3.33, 1.52) and −1.83 ms (95% CI −4.19, 0.54) with rivaroxaban 45 mg and 15 mg, respectively. QTcF was not prolonged with rivaroxaban at any time, and the frequency of outlying results with rivaroxaban and placebo was similar.Conclusion: This thorough QT study, which was performed in accordance with ICH E14 guidelines, shows that rivaroxaban does not prolong the QTc interval. Therefore, the potential of rivaroxaban for the prevention and treatment of thromboembolic disorders, including chronic cardiovascular disorders, can be investigated in appropriate clinical studies without the need for intensive monitoring of the QTc interval.