Pharmacokinetics Of Rivaroxaban Research Articles

A Cross-Study Analysis Evaluating the Effects of Food on the Pharmacokinetics of Rivaroxaban in Clinical Studies.

US prescribing guidelines recommend that 15‐ and 20‐mg doses of rivaroxaban be administered with food for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and for reduction in the risk of recurrence of DVT and PE. In addition, the US prescribing guidelines recommend these doses be administered with an evening meal to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). The purpose of this model‐based cross‐study comparison was to examine the impact of food, with regard to both meal timing and content, on the pharmacokinetics (PK) of rivaroxaban, using data collected during its clinical development. Results of this analysis showed that a PK model built from pooled data in the AF population (for whom rivaroxaban was administered with an evening meal) and in the DVT population (for whom rivaroxaban was administered with a morning meal) can describe both data sets well. Furthermore, the PK model built from data in the AF population alone can adequately predict the PK profile of the DVT population and vice versa. This cross‐study analysis also confirmed the findings from previous clinical pharmacology studies, which showed that meal content does not have a clinically relevant impact on the PK of rivaroxaban at 20 mg. Therefore, although the administration of rivaroxaban with food is necessary for maintaining high bioavailability, neither meal timing nor meal content appears to affect the PK of rivaroxaban.

Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB1 genetic polymorphisms and interaction with clarithromycin

Background The direct oral anticoagulants (DOACs) dabigatran and rivaroxaban are both substrates of the P-glycoprotein (P-gp) transporter, encoded by the ABCB1 gene. Rivaroxaban is metabolized by cytochrome P450 A4 (CYP3A4). Interindividual variability in DOAC exposure and frequent P-gp-associated drug-drug interactions have been described in patients. Objective To assess the influence of ABCB1 polymorphisms on the pharmacokinetics of dabigatran and rivaroxaban, associated or not with clarithromycin, a P-gp and CYP3A4 inhibitor. Methods Sixty healthy male volunteers, selected according to ABCB1 genotype (20 homozygous mutated, 20 heterozygous mutated, and 20 wild-type for haplotype 2677-3435), were included in this randomized, two-center, crossover study. All received sequentially a single dose of dabigatran etexilate (300 mg) and rivaroxaban (40 mg) associated or not with clarithromycin. Peak plasma concentration and area under the curve (AUC) were compared across the three ABCB1 genotypes. The effect of clarithromycin on dabigatran or rivaroxaban pharmacokinetics was assessed. Results Interindividual coefficients of variation for AUC were 77% for dabigatran and 51% for rivaroxaban. ABCB1 genotype did not significantly affect drug pharmacokinetics: AUC ratios between mutant-allele carriers and wild-type volunteers were 1.27 (95% confidence interval [CI] 0.84-1.92) and 1.20 (95% CI 0.96-1.51) for dabigatran and rivaroxaban, respectively. Clarithromycin coadministration led to a two-fold increase in both drugs' AUC, irrespective of ABCB1 genotype: ratios of geometric means were 2.0 (95% CI 1.15-3.60) and 1.94 (95% CI 1.42-2.63) for dabigatran and rivaroxaban, respectively. Conclusions ABCB1 genotype is not a significant determinant of interindividual variability in dabigatran and rivaroxaban pharmacokinetics. The levels of one drug did not predict the levels of the other. Coadministration of a P-gp/CYP3A4 inhibitor with dabigatran or rivaroxaban may warrant caution in patients at risk of overexposure.

PHARMACOGENETIC ASPECTS OF NEW ORAL ANTICOAGULANTS APPLICATION

The aim of this review is to assess the effect of genetic factors on the pharmacokinetic parameters of new oral anticoagulants. The review presents data from studies investigating the effect of gene polymorphisms that encode biotransformation enzymes and transporter proteins of new oral anticoagulants on the pharmacokinetics of these drugs. RE-LY study showed a 15% decrease in trough dabigatran concentration and 27% lower risk of bleeding in carriers of CES1 gene rs2244613 polymorphism, there was also a tendency to reduce the risk of major bleeding. Further study of CES1 gene rs8192935 polymorphism showed a 3% decrease in trough dabigatran concentration in heterozygotes and 11% in homozygotes. There was found a 2% and 3% decrease in trough concentrations in hetero- and homozygotes for the minor allele of CES1 gene rs2244613 polymorphism, respectively. There was no significant effect of ABCB1 gene rs2032582 and rs1045642 polymorphisms on dabigatran pharmacokinetics. It is known the case of gastrointestinal bleeding in the carrier of allelic variants of ABCB1 gene rs2032582 and rs1045642 polymorphisms. However, there was no significant effect of genotype on rivaroxaban pharmacokinetics in the study involving the carriers of ABCB1 gene rs2032582 and rs1045642 polymorphisms. ABCB1 gene rs4148738 polymorphism was associated with higher apixaban peak concentration. But groups of patients with acute cardioembolic stroke showed no statistically significant difference of apixaban peak concentration depending on ABCB1 gene rs1045642 polymorphism genotype. ABCB1 gene rs1045642 and SLCO1B1 gene rs4149056 polymorphisms have no effect on edoxaban pharmacokinetics. Elevation of edoxaban metabolite concentration in carriers of SLCO1B1 gene allelic variants was not clinically significant because the proportion of metabolite is about 10% of the concentration of the main substance. It is necessary to provide large population studies with control of treatment efficacy and safety to prove clinical significance of genotyping for new oral anticoagulants use.

Rivaroxaban-Induced Hemorrhage Associated with ABCB1 Genetic Defect.

We report a patient who presented a non-ST segment elevation myocardial infarction in the context of severe normocytic hypochromic anemia related to gastrointestinal bleeding, 3 months after switching anticoagulant from the vitamin K antagonist acenocoumarol to the direct oral anticoagulant rivaroxaban. High levels of both anti-Xa activity and rivaroxaban plasma concentrations were measured despite rivaroxaban withdrawal, suggesting reduced elimination/drug clearance. Estimated half-life was 2–3 times longer than usually reported. The patient is a homozygous carrier of ABCB1 variant alleles, which could have participated to reduced elimination of rivaroxaban. Furthermore, CYP3A4/5 phenotyping showed moderately reduced enzyme activity. Drug-drug interaction with simvastatin may have contributed to decreased rivaroxaban elimination. Although in the present case moderate acute renal failure probably played a role, more clinical data are required to elucidate the impact of ABCB1 polymorphism on rivaroxaban pharmacokinetics and bleeding complications.

Pharmacokinetic and pharmacodynamic evaluation of oral rivaroxaban in healthy adult cats.

To determine the pharmacodynamics and pharmacokinetics of rivaroxaban (RVX), in healthy cats and to evaluate the clinicopathologic effects of various plasma RVX concentrations within target therapeutic ranges established for people. Prospective randomized cross-over study performed between July 2013 and November 2014. Veterinary university teaching hospital. Six healthy adult domestic shorthair cats (3 males, 3 females). Cats were treated with oral RVX at single, fixed doses (1.25, 2.5, 5 mg PO), q 12 h for 3 days (1.25 mg); q 24 h for 7 days (2.5 mg); and q 24 h for 28 days (1.25 mg). Blood samples were collected for complete blood count, blood chemistry, and RVX anticoagulant activity based on prolongation of dilute prothrombin time, activated partial thromboplastin time (aPTT), activated Factor X (FXa) inhibition (anti-Xa activity [aXa]) and high-pressure liquid chromatography tandem mass spectrometry determination of drug concentration. Treated cats had no signs of hemorrhage or clinicopathologic off-target adverse effects. There were dose-dependent prolongations of coagulation times and increase in aXa, with peak effect at 3 hours postadministration. There was a direct correlation between plasma RVX concentration and dilute prothrombin time and aXa. Coagulation parameters returned to baseline by 24 hours after the last dose. Oral RVX was well tolerated by healthy cats with predictable pharmacokinetics and anticoagulant effects. Clinical studies of RVX are warranted in cats with heart disease.

Treatment of venous thromboembolism with rivaroxaban in relation to body weight. A sub-analysis of the EINSTEIN DVT/PE studies.

The pharmacokinetics of oral rivaroxaban are highly predictable and only affected to a limited extent by bodyweight; therefore, dose adjustments for bodyweight are not required. However, this raises concerns among physicians for potential under- or overdosing. This substudy of the randomised EINSTEIN DVT and EINSTEIN PE trials, which compared rivaroxaban with enoxaparin/vitamin K antagonist (VKA) therapy, aimed to determine the incidence of major bleeding in patients with a low bodyweight and recurrent venous thromboembolism (VTE) in patients with a high bodyweight during rivaroxaban or enoxaparin/VKA therapy. More than 8,000 patients with objectively diagnosed deep-vein thrombosis or pulmonary embolism were included. Adjusted hazard ratios for recurrent VTE and bleeding were calculated using the Cox proportional hazards model. Analyses were performed for both the first 21 days of treatment and the whole treatment period. For rivaroxaban recipients, there was no association between bodyweight or body mass index (BMI) and risk of recurrent VTE (ptrend=0.87 and 0.62, respectively), major bleeding (ptrend=0.24 and 0.36, respectively) or clinically relevant bleeding (ptrend=0.17 and 0.63, respectively). Major bleeding events were numerically lower in rivaroxaban patients across all bodyweight and BMI categories. Hazard ratios for rivaroxaban vs enoxaparin/VKA were similar in all bodyweight and BMI categories, both during the first 21 days and the whole treatment period. The fixed-dose rivaroxaban regimen is not associated with an increased risk of major bleeding or recurrent VTE in patients with either a low or high bodyweight. A high BMI was not associated with an increased risk of recurrent VTE during anticoagulation.

Rivaroxaban transfer across the dually perfused isolated human placental cotyledon

The purpose of this study was to determine the rate and extent of rivaroxaban transfer across the term human placenta and determine whether passive diffusion was the primary mechanism involved in this transfer. The transplacental pharmacokinetics of rivaroxaban was determined with the ex-vivo placenta perfusion model. Rivaroxaban was added to the maternal or fetal circulation only (250 ng/mL). Additional experiments were conducted under equilibrative conditions with the addition of rivaroxaban to both the maternal and fetal circulations (250 ng/mL). Rivaroxaban concentrations were measured with the use of liquid chromatography-tandem mass spectrometry. There was rapid transfer of rivaroxaban across the human placenta in both the maternal-to-fetal and fetal-to-maternal directions, as evidenced by transfer ratios of 0.69 (interquartile range, 0.58-0.73; n = 5) and 0.69 (interquartile range, 0.67-0.71; n = 2), respectively, after 3 hours. Under equilibrative conditions (n = 2), rivaroxaban concentrations remained relatively constant, which suggests that rivaroxaban crosses the placenta down a concentration gradient. This is the first direct evidence of rivaroxaban transfer across the term human placenta from both the mother-to-fetus and fetus-to-mother directions. Our results document that unbound rivaroxaban rapidly crosses the placental barrier via passive diffusion. However, because rivaroxaban is highly bound to plasma proteins (up to 95%), this suggests that the amount of unbound drug that may reach the fetus is likely much lower. Additional studies will need to explore its safety before administering rivaroxaban to a pregnant woman.

Rivaroxaban use following bariatric surgery

The recent case report by Dr. Mahlmann et al. [1] describing the pharmacokinetics of rivaroxaban in a bariatric surgery patient is a welcome addition to the literature. However, we feel it necessary to clarify the statement made regarding the ‘‘high bioavailability’’ of rivaroxaban and express caution regarding the use of this agent in postoperative bariatric surgery patients. The bioavailability of rivaroxaban depends on the dose and also the presence of food. Studies have shown that rivaroxaban doses up to 10 mg have high bioavailability. However, higher doses, which are employed for the prevention of stroke in atrial fibrillation and the treatment of venous thromboembolism (VTE), have poor bioavailability (*66 % for a 20 mg dose) [2, 3]. In pharmacokinetic studies, the bioavailability of higher doses is markedly improved (C80 %) when taken with food [2]. For this reason, the rivaroxaban prescribing information states that it should be taken ‘‘with food’’ for the atrial fibrillation and VTE treatment indications [4]. ‘‘With food’’ is a rather vague description with interpretations ranging from ‘‘take with a small snack’’ to ‘‘take with a full meal.’’ In the ROCKET–AF trial, patients were instructed to take their dose with their evening meal, but no specific calorie or size requirements were specified [5]. In the VTE treatment studies, patients were instructed to take their doses with meals with no further specifications [6, 7]. In the previously mentioned pharmacokinetic studies, ‘‘with food’’ was specifically a large meal of approximately 1,000 kcal [2]. While it is doubtful that subjects receiving rivaroxaban in clinical trials took their doses with such a large caloric intake, it seems reasonable to presume their doses were taken with standard meals and that their caloric intake was essentially normal (*1,800–2,500 kcal per day in the USA) [8]. Venous thromboembolism is a cause of morbidity and mortality after gastric bypass surgery and obesity increases the risk of atrial fibrillation [9, 10]. The relative ease of rivaroxaban compared to traditional agents may make it an attractive option for patients experiencing these events after bariatric surgery. To our knowledge, there are no clinical trial data to support the use of rivaroxaban for these indications specifically in bariatric surgery patients. Although the report by Mahlmann et al. [1] and a previous study that suggests that rivaroxaban is not influenced by extremes of weight [11] offers some reassurance, other factors must be considered before rivaroxaban is used in these patients. Specifically, we believe that patients who are in the early postoperative period after bariatric surgery should not receive rivaroxaban for either the atrial fibrillation or VTE treatment indications due to the low caloric intake (*500 calories per day) that is characteristic of the diets that these patients are placed on postoperatively [12]. In Dr. Mahlmann’s report [1], rivaroxaban was started several months after bariatric surgery and thus this patient’s caloric intake would likely have been much closer to normal relative to the postoperative period. Since the minimum amount of food required ensuring adequate absorption of rivaroxaban has not been determined, it is quite plausible that the low calorie consumption of the postoperative gastric bypass patient is insufficient to support adequate rivaroxaban absorption. Furthermore, Z. Thomas (&) Y. Bareket W. Bennett Hackensack University Medical Center, 30 Prospect Avenue, Hackensack, NJ 07601, USA e-mail: zthomas@rci.rutgers.edu

Phamacokinetics of rivaroxaban in adolescents

The direct factor Xa inhibitor rivaroxaban is approved for venous thromboembolism (VTE) treatment in adults. However, in all phase-III trials children or adolescents have not been included. For under-aged VTE patients, current standard treatment consists of low molecular weight heparin or Vitamin K antagonists. Rivaroxaban could be an attractive alternative, however, no data on the pharmacokinetics (PK) of rivaroxaban in adolescents are currently available. PATIENT, METHODS: We report PK data for rivaroxaban derived from a girl (age:15 years), who presented three month after acute deep vein thrombosis, already receiving rivaroxaban therapy. In the steady state of rivaroxaban therapy (20 mg once daily), plasma levels at baseline, 3 and 6 hours after intake of rivaroxaban were measured to evaluate the pharmacokinetics and changes of global coagulation tests. At baseline, a very low trough level of only 9.9 ng/ml rivaroxaban was found. At 3 hours, a peak concentration of 137.76 ng/ml rivaroxaban was observed with a rapid decrease within 6 hours after drug intake, when plasma levels of 34.45 ng/ml were measured. The patients INR and aPTT values reacted correspondingly. Our data indicate that adolescents may exhibit lower peak and trough levels after rivaroxaban intake compared to adult patients, but seem to have similar PK curves during the elimination phase. While our case is the first published case of a successful VTE treatment in an under-aged patient, we strongly discourage the routine use of rivaroxaban in non-adult patients, until data from phase II and III trials are available.

Development of a Paediatric Population-Based Model of the Pharmacokinetics of Rivaroxaban

BackgroundVenous thromboembolism has been increasingly recognised as a clinical problem in the paediatric population. Guideline recommendations for antithrombotic therapy in paediatric patients are based mainly on extrapolation from adult clinical trial data, owing to the limited number of clinical trials in paediatric populations. The oral, direct Factor Xa inhibitor rivaroxaban has been approved in adult patients for several thromboembolic disorders, and its well-defined pharmacokinetic and pharmacodynamic characteristics and efficacy and safety profiles in adults warrant further investigation of this agent in the paediatric population.ObjectiveThe objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for rivaroxaban doses of 10 and 20 mg in adults and to scale this model to the paediatric population (0–18 years) to inform the dosing regimen for a clinical study of rivaroxaban in paediatric patients.MethodsExperimental data sets from phase I studies supported the development and qualification of an adult PBPK model. This adult PBPK model was then scaled to the paediatric population by including anthropometric and physiological information, age-dependent clearance and age-dependent protein binding. The pharmacokinetic properties of rivaroxaban in virtual populations of children were simulated for two body weight-related dosing regimens equivalent to 10 and 20 mg once daily in adults. The quality of the model was judged by means of a visual predictive check. Subsequently, paediatric simulations of the area under the plasma concentration–time curve (AUC), maximum (peak) plasma drug concentration (C max) and concentration in plasma after 24 h (C 24h) were compared with the adult reference simulations.ResultsSimulations for AUC, C max and C 24h throughout the investigated age range largely overlapped with values obtained for the corresponding dose in the adult reference simulation for both body weight-related dosing regimens. However, pharmacokinetic values in infants and preschool children (body weight <40 kg) were lower than the 90 % confidence interval threshold of the adult reference model and, therefore, indicated that doses in these groups may need to be increased to achieve the same plasma levels as in adults. For children with body weight between 40 and 70 kg, simulated plasma pharmacokinetic parameters (C max, C 24h and AUC) overlapped with the values obtained in the corresponding adult reference simulation, indicating that body weight-related exposure was similar between these children and adults. In adolescents of >70 kg body weight, the simulated 90 % prediction interval values of AUC and C 24h were much higher than the 90 % confidence interval of the adult reference population, owing to the weight-based simulation approach, but for these patients rivaroxaban would be administered at adult fixed doses of 10 and 20 mg.ConclusionThe paediatric PBPK model developed here allowed an exploratory analysis of the pharmacokinetics of rivaroxaban in children to inform the dosing regimen for a clinical study in paediatric patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-013-0090-5) contains supplementary material, which is available to authorized users.

The effect of food on the absorption and pharmacokinetics of rivaroxaban

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. Rivaroxaban was obtained from Bayer Pharma AG, Wuppertal, Germany. 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. 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. 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.

Investigation of Pharmacodynamic and Pharmacokinetic Interactions Between Rivaroxaban and Enoxaparin in Healthy Male Subjects.

Rivaroxaban, an oral, direct factor Xa inhibitor, is currently used in clinical practice for the prevention and treatment of thromboembolic disorders. This single-center, three-way crossover study was designed to investigate the pharmacodynamic effects of rivaroxaban (10 mg) and enoxaparin (40 mg) alone and in combination as well as the influence of enoxaparin on the pharmacokinetics of rivaroxaban in healthy male subjects. When given alone, both drugs exhibited similar, rapid anti-factor Xa activity. Combined administration resulted in an increase of ∼50% in anti-factor Xa activity and a lesser increase in activated partial thromboplastin time, compared with either drug alone. Enoxaparin had no additional effect on prolongation of the prothrombin time induced by rivaroxaban and did not affect the pharmacokinetic parameters of rivaroxaban. The results showed that rivaroxaban (10 mg) and enoxaparin (40 mg) had a similar and rapid onset of action, as indicated by the similar anti-factor Xa activity-time curves, suggesting that both drugs have a similar duration of pharmacological activity at the factor X site. Co-administration of rivaroxaban and enoxaparin is associated with enhanced pharmacodynamic effects.

Pharmacology of the new target-specific oral anticoagulants

Oral anticoagulation therapy is transforming with the advent of the target specific oral anticoagulants, particularly, the direct thrombin inhibitors and factor Xa inhibitors. These agents have demonstrated clinical efficacy and safety and offer several potential advantages over current standard of care therapy, warfarin. Nevertheless, the pharmacology between the newly approved oral anticoagulants differs and must be considered for appropriate management and patient selection. The pharmacodynamics and pharmacokinetics of dabigatran etexilate, rivaroxaban, apixaban and edoxaban are discussed in detail, which may translate into considerable clinical implications.

Pharmacokinetics of rivaroxaban after bariatric surgery: a case report

Rivaroxaban is a direct factor Xa inhibitor, which is rapidly absorbed in the upper gastrointestinal (GI) tract. In large trials, it has been shown to be effective and safe in VTE treatment. However, in these trials patients with morbid obesity were not reported and it is unknown if the standard dosage of 20 mg rivaroxaban is sufficient for bariatric patients, especially after bariatric surgery, which may impact the resorption of rivaroxaban. We report the case of a bariatric patient with high venous thromboembolism risk and instable INR after recent bariatric surgery, who was switched from Vitamin-K antagonists to rivaroxaban. After intake of 20 mg rivaroxaban, plasma concentration were repeatedly measured until 3 h after the second dose using a commercially available chromogenic aXa-assay. Furthermore, INR and aPTT were measured. Peak concentrations of 224.22 ng/ml were observed. After 6 h, plasma concentration decreased to 86.9 ng/ml and remained stable until 12 h (86.32 ng/ml). After 24 h, a trough level of 35.54 ng/ml was observed. The patients INR did immediately increase and remained significantly elevated throughout the day with a slow decrease. Since peak values of rivaroxaban plasma concentrations were in the expected range of published data, we conclude that resorption of rivaroxaban was immediate and not significantly impaired by bariatric surgery of the upper GI tract. Consequently, no dose adjustments seem to be necessary in this high-risk population.

Model-based Dose Selection for Phase III Rivaroxaban Study in Japanese Patients with Non-valvular Atrial Fibrillation

The global ROCKET AF phase III trial evaluated rivaroxaban 20 mg once daily (o.d.) for stroke prevention in atrial fibrillation (AF). Based on rivaroxaban pharmacokinetics in Japanese subjects and lower anticoagulation preferences in Japan, particularly in elderly patients, the optimal dose regimen for Japanese AF patients was considered. The aim of this analysis was dose selection for Japanese patients from a pharmacokinetic aspect by comparison of simulated exposure in Japanese patients with those in Caucasian patients. As a result of population pharmacokinetics-pharmacodynamics analyses, a one-compartment pharmacokinetic model with first-order absorption and direct link pharmacokinetic-pharmacodynamic models optimally described the plasma concentration and pharmacodynamic models (Factor Xa activity, prothrombin time, activated partial thromboplastin time, and HepTest), which were also consistent with previous works. Steady-state simulations indicated 15 mg rivaroxaban o.d. doses in Japanese patients with AF would yield exposures comparable to the 20 mg o.d. dose in Caucasian patients with AF. In conclusion, in the context of the lower anticoagulation targets in Japanese practice, the population pharmacokinetic and pharmacodynamic modeling supports 15 mg o.d. as the principal rivaroxaban dose in J-ROCKET AF.

Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring

Unlike traditional anticoagulants, the more recently developed agents rivaroxaban, dabigatran and apixaban target specific factors in the coagulation cascade to attenuate thrombosis. Rivaroxaban and apixaban directly inhibit Factor Xa, whereas dabigatran directly inhibits thrombin. All three drugs exhibit predictable pharmacokinetic and pharmacodynamic characteristics that allow for fixed oral doses in a variety of settings. The population pharmacokinetics of rivaroxaban, and also dabigatran, have been evaluated in a series of models using patient data from phase II and III clinical studies. These models point towards a consistent pharmacokinetic and pharmacodynamic profile, even when extreme demographic factors are taken into account, meaning that doses rarely need to be adjusted. The exception is in certain patients with renal impairment, for whom pharmacokinetic modelling provided the rationale for reduced doses as part of some regimens. Although not routinely required, the ability to measure plasma concentrations of these agents could be advantageous in emergency situations, such as overdose. Specific pharmacokinetic and pharmacodynamic characteristics must be taken into account when selecting an appropriate assay for monitoring. The anti-Factor Xa chromogenic assays now available are likely to provide the most appropriate means of determining plasma concentrations of rivaroxaban and apixaban, and specific assays for dabigatran are in development.

Laboratory assessment of rivaroxaban: a review

Research into new anticoagulants for preventing and treating thromboembolic disorders has focused on targeting single enzymes in the coagulation cascade, particularly Factor Xa and thrombin, inhibition of which greatly decreases thrombin generation. Based on the results of phase III clinical trials, rivaroxaban, a direct Factor Xa inhibitor, has been approved in many countries for the management of several thromboembolic disorders. Owing to its predictable pharmacokinetic and pharmacodynamic characteristics, fixed-dose regimens are used without the need for routine coagulation monitoring. In situations where assessment of rivaroxaban exposure may be helpful, anti-Factor Xa chromogenic assays (in tandem with standard calibration curves generated with the use of rivaroxaban calibrators and controls) could be used. It is important to note that test results will be affected by the timing of blood sampling after rivaroxaban intake. In addition, the anti-Factor Xa method measures the drug concentration and not the intensity of the drug’s anticoagulant activity, and a higher than expected rivaroxaban plasma level does not necessarily indicate an increased risk of bleeding complications. Therefore, clinicians need to consider test results in relation to the pharmacokinetics of rivaroxaban and other patient risk factors associated with bleeding.

Drug Interactions with Rivaroxaban following Total Joint Replacement Surgery

To evaluate potential drug-drug interactions with rivaroxaban in patients undergoing total hip replacement (THR) and total knee replacement (TKR) surgeries. PubMed; January 2009-April 2012 abstract databases of major congresses for hematology and cardiovascular medicine. Searches were performed using the key words rivaroxaban and drug interaction. Studies were included if they evaluated interactions with drugs that are commonly used in patients undergoing THR or TKR, based on our clinical experience. A Phase 1 study found that coadministration of rivaroxaban and the nonsteroidal antiinflammatory drug (NSAID) naproxen significantly increased bleeding time. However, in a retrospective analysis of 4 large trials evaluating rivaroxaban in patients undergoing THR or TKR, the difference between major and clinically relevant nonmajor bleeding was not significantly different between NSAID users and nonusers. In addition, proton pump inhibitors, which are frequently coadministered with NSAIDs to prevent gastrointestinal toxicity, have not been demonstrated to cause any appreciable changes in rivaroxaban pharmacokinetics or pharmacodynamics. A Phase 2 study that evaluated several doses and administration intervals of rivaroxaban in combination with aspirin or both aspirin and clopidogrel in patients with acute coronary syndrome found that clinically significant bleeding events occurred in patients receiving rivaroxaban 10 mg daily (the dose approved for the orthopedic indication). However, this risk was not great enough to end the trial early. Phase 1 drug-drug interaction studies in healthy humans provided little insight into the pharmacodynamic drug interactions between rivaroxaban and NSAIDs or antiplatelet agents. A pooled analysis of the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism) trials and data from other large trials provides clinical evidence that these agents can be coadministered with rivaroxaban, as long as proper monitoring is instituted.

Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes

• Population pharmacokinetics and pharmacodynamics of rivaroxaban have been characterized in healthy subjects and in patients with total venous thromboembolism, deep vein thrombosis or atrial fibrillation. • This article is the first description of the population pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in patients with acute coronary syndrome (ACS). It is the largest population pharmacokinetic and pharmacodynamic study on rivaroxaban conducted to date (n= 2290). The PK and PK-PD relationship of rivaroxaban in patients with ACS were similar to those in other patient populations. In addition, model-based simulations showed that the influence of renal function and age on the exposure to rivaroxaban in the ACS population were similar to the findings from Phase 1 special population studies. These findings suggest that rivaroxaban has highly predictable PK-PD and may provide a consistent anticoagulant effect across the studied patient populations, which allows an accurate prediction of the dose to control anticoagulation optimally. The aim of this analysis was to use a population approach to facilitate the understanding of the pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndrome (ACS) and to evaluate the influence of patient covariates on the exposure of rivaroxaban in patients with ACS. METHODS A population pharmacokinetic model was developed using pharmacokinetic samples from 2290 patients in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46. The relationship between pharmacokinetics and the primary pharmacodynamic end point, prothrombin time, was evaluated. The pharmacokinetics of rivaroxaban in patients with ACS was adequately described by an oral one-compartment model. The estimated absorption rate, apparent clearance and volume of distribution were 1.24 h(-1) (interindividual variability, 139%), 6.48 l h(-1) (31%) and 57.9 l (10%), respectively. Simulations indicate that the influences of renal function, age and bodyweight on exposure in ACS patients are consistent with the findings in previous Phase 1 studies. Rivaroxaban plasma concentrations exhibit a close-to-linear relationship with prothrombin time in the ACS population, with little interindividual variability. The estimated pharmacokinetic and pharmacodynamic parameters for the ACS patients were comparable to those for venous thromboembolism prevention, deep vein thrombosis and atrial fibrillation patients. The similarity in pharmacokinetics/pharmacodynamics of rivaroxaban among different patient populations and the low interindividual variability in the exposure-prothrombin time relationship indicate that the anticoagulant effect of rivaroxaban is highly predictable and consistent across all the patient populations studied.

Pharmacokinetic evaluation of rivaroxaban for the treatment of acute coronary syndromes

Introduction: Arterial and venous thrombotic states, including myocardial infarction (MI), stroke and deep vein thrombosis with subsequent pulmonary embolism, are a significant cause of cardiovascular mortality and morbidity. Factor Xa (FXa) plays a pivotal role in thrombus formation. Its inhibition following acute coronary syndromes (ACS) blocks amplification of thrombin generation and subsequent clot formation, resulting in a risk reduction in recurrent MI, stroke and death. For this reason, a predictable form of oral anticoagulation continues to be an ongoing need. Rivaroxaban, the first oral FXa inhibitor, acts by direct inhibition of FXa and does not require an antithrombin cofactor for its activity.Areas covered: This paper describes the pharmacokinetics (PK) of low-dose rivaroxaban tested in patients with ACS. Age, gender, renal function and body weight have no clinically significant effects on the PK of the drug in treatment of ACS. Caution should be maintained during co-administration of strong CYP3A4 inducers and inhibitors. Among patients with moderate and severe hepatic impairment and in those with associated coagulopathies, rivaroxaban however is contraindicated.Expert opinion: The mortality benefit with low-dose rivaroxaban in ACS patients was first demonstrated in ATLAS ACS2 TIMI-51 trial. With its rapid oral bioavailability, predictable PK, low drug–drug interaction and no need for monitoring, the use of low-dose rivaroxaban in addition to dual antiplatelet therapy offers an appealing new option in improving outcomes following ACS in the modern era of novel oral FXa inhibitors.