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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Clinical Pharmacology (Dr Kubitza, Dr Zuehlsdorf, Dr Mueck) and the Department of Biometry, Pharmacometry (Dr Becka), Bayer HealthCare AG, Wuppertal, Germany.
Address for reprints: Address for correspondence: Dagmar Kubitza, Bayer HealthCare AG, Building 429, Aprather Weg 18a, Wuppertal, D-42096, Germany.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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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 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.
Key Words: Factor Xa inhibitors • body weight • gender • rivaroxaban • BAY 59-7939
Obesity is well recognized as a major healthcare problem in Western societies and is increasing in the population at an alarming rate.4,5 There is a strong link between obesity and cardiovascular conditions, including atrial fibrillation and acute coronary syndrome, as well as a link to osteoarthritis, causing an increased requirement for joint replacement surgery in obese patients.6,7 Furthermore, elderly patients—who are often frail and underweight—are more likely than the general population to have a condition requiring anticoagulant therapy, such as atrial fibrillation.8 These underweight and overweight patients are in danger of being overanticoagulated or underanticoagulated when inappropriate anticoagulant doses are given and are thus exposed to the associated risks of VTE, stroke, myocardial infarction, or excessive bleeding. New, oral anticoagulants that do not require dose adjustment for body weight would therefore offer considerable benefits to both physicians and patients.
Rivaroxaban (BAY 59-7939) is a novel, oral, direct factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of VTE, and the prevention of stroke in atrial fibrillation. Results of phase 1 studies have shown that rivaroxaban is well tolerated in healthy human subjects, with predictable, doseproportional pharmacokinetics and pharmacodynamics; an elimination half-life of 5 to 9 hours; and no relevant accumulation after multiple, twice-daily dosing.9,10 Phase 2 clinical studies of rivaroxaban for the prevention of VTE after major orthopedic surgery with rivaroxaban have recently been completed: rivaroxaban total daily doses of 5 to 20 mg administered twice daily had similar efficacy and safety to the LMWH enoxaparin.11,12 A further study showed that rivaroxaban 10 mg administered once daily is the optimum dosage in this indication.13 Further studies in VTE prevention and VTE treatment are ongoing.
The objective of this study was to investigate the influence of extremely low and high body weight on the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single 10-mg dose of rivaroxaban in healthy male and female subjects, to provide information on how the pharmacokinetics and pharmacodynamics of rivaroxaban may be affected in patients with extreme body weight. The effect of gender on these parameters was also investigated.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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50 kg, 70 to 80 kg, or >120 kg and aged between 18 and 55 years were enrolled. Female subjects were required to be using 2 forms of nonhormonal contraception or be postmenopausal. Subjects were screened 14 days before the study commenced and were excluded if they had any known coagulation disorders (eg, von Willebrand disease, hemophilias) or conditions with an increased bleeding risk (eg, hemorrhoids, peptic ulcer, acute gastroenteritis, or sensitivity to nasal bleeding). Subjects were randomized to receive a single 10-mg dose of rivaroxaban (Bayer HealthCare AG, Wuppertal, Germany) or placebo in a 3:1 ratio, so that 12 subjects in each weight group received rivaroxaban and 4 received placebo. This dose of rivaroxaban was chosen because it has substantial and measurable pharmacodynamic effects in healthy subjects.9,10 It is also within the range of clinically effective doses observed in the phase 2 clinical studies of rivaroxaban for the prevention of VTE after major orthopedic surgery (5-20 mg total daily dose).11-13
Subjects entered the trial unit the evening before study drug administration. After an overnight fast, the study drug was administered with a standardized continental breakfast. Treatment consisted of a single treatment day, 2 follow-up days, and then discharge. Subjects returned for an end-of-study visit 1 to 2 weeks later.
The study was conducted in accordance with the Declaration of Helsinki, German drug law, the International Conference on Harmonisation guidelines on Good Clinical Practice, and with the approval of the local ethics committee.
Safety and Tolerability Assessments
Subjective tolerability was evaluated by questioning subjects about any adverse events and by subjects spontaneously reporting them. Objective tolerability was assessed by monitoring heart rate, blood pressure and electrocardiograms, clinical hematology and chemistry measurements, and urinalysis. Heart rate, blood pressure, and electrocardiograms were measured at time of study drug administration and 1, 2, 3, 4, 6, 8, 12, 15, 24, and 48 hours thereafter; all other assessments were performed once daily. Adverse events were classified according to their severity using MedDRA.
Pharmacokinetic Assessments
Blood samples for the pharmacokinetic analysis of rivaroxaban were collected in tubes containing ammonium heparinate through an indwelling catheter in the antecubital vein on the profile day and by venipuncture at other times. Samples were taken at the time of study drug administration and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 24, and 48 hours thereafter and were centrifuged to obtain plasma. Urine samples for pharmacokinetic analyses were collected 0 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 hours after drug administration. Rivaroxaban concentrations were determined using a fully validated high-performance liquid chromatography/tandem mass spectrometer method after solid-phase extraction. Monitored ions were 436 
145 (rivaroxaban) and 464 145 (internal standard; 5-chloro-N-({3-[3,5-dimethyl-4-(3-oxomorpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide; Bayer HealthCare AG).14 The lower limit of quantification (LLOQ) for plasma samples was 0.5 µg/L. Samples greater than this concentration were determined with an accuracy of 95.2% to 99.9% and a precision of 2.7% to 6.7%. Urine samples greater than the LLOQ of 0.01 mg/L were determined with an accuracy of 93.2% to 97.7% and a precision of 4.2% to 8.6%. Samples were stored at -15°C and were analyzed within 4 weeks. The primary pharmacokinetic parameters analyzed were area under the concentration-time curve from zero to infinity (AUC) calculated using the loglinear trapezoidal rule and maximum concentration (Cmax) calculated directly from the observations; these were assessed assuming log-normally distributed data. Secondary parameters analyzed included AUC and Cmax normalized to dose and body weight (AUCnorm, Cmax,norm), time of Cmax (tmax), the half-life of rivaroxaban associated with the terminal slope (t
), and apparent volume of distribution during the terminal phase after oral administration (Vz/F).
Pharmacodynamic Assessments
Samples to assess the effects of rivaroxaban on FXa activity, prothrombin time (PT), activated partial thromboplastin time (aPTT), and HepTest were collected into tubes containing sodium citrate at the same time points as the samples for the pharmacokinetic analysis. FXa activity was determined by a 2-step photometric assay: factor X in plasma was completely activated with Russell's viper venom in the presence of calcium ions; the chromogenic substrate ZD-Arg-Gly-Arg-pNA (S-2765TM; Chromogenix, Milan, Italy) was then hydrolyzed by FXa, releasing pNA, which was quantified by spectrophotometry at 405 nm. Standards and controls were prepared from the Third International Standard Coagulation Factors II and X Concentrate, Human 98/590 (National Institute for Biological Standards and Control, Potters Bar, UK). Concentrations greater than 0.1 I U/mL (LLOQ) were determined with a precision of 9.5% to 14% and an accuracy of 99.5% to 114%. The PT was assessed using freeze-dried thromboplastin from rabbit brain (Neoplastin Plus; Roche Diagnostics, Mannheim, Germany), and aPTT was assessed using a kaolin-activated test (Roche Diagnostics). The PT, aPTT, and HepTest (Haemachem, St Louis, Mo) were measured using a ball coagulometer KC 10 (Amelung, Germany) according to the manufacturer's instructions.
FXa activity at the time of study drug administration (time 0) was designated 0% inhibition; values after drug administration were converted to percentage inhibition. The PT at time 0 was taken as baseline, and values after drug administration, relative to baseline, were calculated as "times baseline." From these values, noncompartmental kinetic parameters were calculated: area under the effect-time curve from the first to last reading (AUC0-tn) and maximum effect of this dose (Emax).
Statistical Evaluation
Weight and gender differences between groups for the AUC and Cmax of rivaroxaban and the baseline adjusted AUC0-tn and Emax of inhibition of FXa activity and prolongation of PT were investigated using exploratory analysis of variance (ANOVA) of the logtransformed data, including the factors weight category and gender as well as their interaction. Point estimates (least squares [LS]-means ratios) and 90% confidence intervals (CIs) for weight and gender categories were calculated by retransformation of the logarithmic data.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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50 kg group was composed of women only because it was not possible to find healthy, adult, Caucasian, male subjects with such a low body weight. Subjects' demographics are shown in Table I. Subjects were well matched with respect to age, and the 70 to 80 kg and >120 kg groups were of similar heights.
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Safety and Tolerability
There were no serious adverse events after administration of rivaroxaban, and no adverse events were reported in the placebo group. Twenty-one treatmentemergent adverse events were reported by 12 subjects receiving rivaroxaban. The number of subjects reporting adverse events was similar in the 3 groups, as was the total number of adverse events reported: 9 events reported by 5 subjects in the 50 kg group, 6 events reported by 3 subjects in the 70 to 80 kg group, and 6 events reported by 4 subjects in the >120 kg group. All adverse events were mild or moderate in intensity, and all resolved by the end of the study.
Fatigue was the most common adverse event, affecting 5 subjects (1, 2, and 2 in the 50 kg, 70-80 kg, and >120 kg groups, respectively); headache occurred in 4 subjects (2 each in the 50 kg and >120 kg groups); dizziness was reported by 3 subjects (2 in the 70-80 kg group and 1 in the >120 kg group); and nausea was reported by 3 subjects (2 in the 50 kg group and 1 in the >120 kg group). No adverse events related to bleeding were observed. Male subjects reported slightly more adverse events than female subjects in the 70 to 80 kg group (5 events compared with 1 event, respectively) and >120 kg group (4 events compared with 2 events). No clinically relevant changes in laboratory parameters associated with rivaroxaban administration were observed. One subject in the 70 to 80 kg group had elevated aspartate aminotransferase (AST; 2.49 times the upper limit of normal [ULN]) and creatine kinase (21.21 times the ULN) levels 7 days after receiving rivaroxaban. The subject had been discharged from the study unit several days before, and the investigator considered that the changes were not related to study medication. AST levels had normalized within 13 days of rivaroxaban administration, and creatine kinase normalized within 25 days.
In general, weight had an influence on all vital signs. At baseline, blood pressure increased with body weight, although it did not exceed the reference range. Heart rate was similar in the 50 kg and 70 to 80 kg groups and was higher in the >120 kg group at baseline. However, vital signs and electrocardiogram readings were not affected by administration of rivaroxaban.
Pharmacokinetics
Subjects in the 50 kg group had higher peak plasma concentrations of rivaroxaban than the other groups (Figure 1A). This was confirmed by the Cmax value, which was significantly increased by 24% (LS-means ratio, 1.24; 90% CI, 1.07-1.44) in this group compared with the 70 to 80 kg group (P = .04; Table II). Cmax values were similar in the >120 kg and 70 to 80 kg groups, with an LS-means ratio that was close to 1 (1.04; 90% CI, 0.90-1.20). AUC was not significantly different among the 3 weight groups (P = .21), as shown by the LS-means ratios, which were 1.14 (90% CI, 0.98-1.30) between the 50 kg and 70 to 80 kg groups and 1.12 (90% CI, 0.98-1.28) between the >120 kg and 70 to 80 kg groups (Table II).
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The tmax of rivaroxaban was not affected by body weight (Table II), whereas the t of rivaroxaban was increased by approximately 2 hours in the 50 kg group compared with the other groups. The apparent volume of distribution (Vz/F) of rivaroxaban was small and decreased slightly with increasing body weight.
Gender did not strongly affect the bioavailability of rivaroxaban (Figure 1B); the LS-means ratios of the AUC and Cmax were all close to 1 (Table II).
Pharmacodynamics
FXa activity was unaffected in subjects receiving placebo. Rivaroxaban inhibited FXa activity to a similar extent in all 3 weight groups (Figure 2A). Emax occurred 3 to 4 hours after rivaroxaban administration. There were no significant differences in Emax between the groups (P = .08), but it was slightly lower in the >120 kg group (Table III). The LS-means ratios for Emax of inhibition of FXa activity were close to 1; they were 1.02 (90% CI, 0.94-1.12) between the 50 kg group and the 70 to 80 kg group and 0.91 (90% CI, 0.80-1.03) between the >120 kg group and the 70 to 80 kg group. All of the CIs were within the interval 0.8 to 1.25, indicating bioequivalence.15 The time course of inhibition of FXa activity followed a similar pattern in all 3 groups, although the return of FXa activity to baseline was slightly slower with increasing weight. This resulted in the AUC0-tn of the inhibition of FXa activity versus time curve increasing with increasing body weight; however, differences between the groups were not significant (P = .07).
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Rivaroxaban prolonged PT, and placebo had no effect (Figure 2B). The Emax for prolongation of PT decreased significantly (P < .001) with increasing body weight, with LS-means ratios of 1.15 (90% CI, 1.01-1.32) between the 50 kg group and the 70 to 80 kg group and 0.82 (90% CI, 0.72-0.94) between the 70 to 80 kg group and the >120 kg group. Maximum prolongation was observed 2 to 3 hours after administration of rivaroxaban, and PT almost completely returned to baseline after 15 hours. The return to baseline was slightly slower with increasing weight, although there were no differences in AUC0-tn for PT prolongation among the groups (P = .69).
Gender comparisons were not possible in the 50 kg weight group because it was composed of women only. Inhibition of FXa activity and prolongation of PT followed a similar pattern in male and female subjects in the 70 to 80 kg and >120 kg groups (Figure 3). Kinetic analysis of these parameters showed that male subjects had higher AUC0-tn values and lower Emax values than female subjects did (Table II), although the LS-means ratios showed that there was no relevant difference between the genders.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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50 kg), extremely high body weight (>120 kg), and a normal body weight group (70-80 kg) for comparison. Equal numbers of men and women were enrolled in the 70 to 80 kg and >120 kg groups; however, it was not possible to find healthy, male Caucasian subjects weighing 50 kg. It was thought acceptable for the 50 kg group to be gender unbalanced because women are considered to be more sensitive to anticoagulants than men are,3 and patients with an extremely low body weight are also more likely to be female. Rivaroxaban was well tolerated; adverse events were mild to moderate in intensity and resolved by the end of the study. The occurrence of adverse events was similar among the 3 weight groups. More male subjects than female subjects reported adverse events in the 70 to 80 kg and >120 kg groups; however, the difference was too small to be clinically meaningful. No adverse events related to the anticoagulant effect of rivaroxaban (such as bleeding or hematomas) were observed in any weight group. Furthermore, there was no evidence of elevations in liver enzymes corresponding to the timing of rivaroxaban administration. Other phase 1 studies have shown that rivaroxaban is well tolerated,9,10 and, importantly, in recent phase 2 clinical studies of rivaroxaban for the prevention of VTE after major orthopedic surgery, no dose adjustment was required for patients with extremes of body weight.11-13
The bioavailability of rivaroxaban, in terms of the AUC of plasma concentrations, was similar in all 3 weight categories; however, the Cmax was increased significantly in the 50 kg weight group compared with the normal-weight and >120 kg groups. The tmax of rivaroxaban was similar in all weight groups, although the t was increased slightly in subjects with a low body weight. The changes in the pharmacokinetics of rivaroxaban observed in subjects with low body weight were small and, because of the wide therapeutic window observed for rivaroxaban in clinical studies,11-13 were considered unlikely to be clinically relevant. Gender did not affect the bioavailability of rivaroxaban in normal-weight subjects. There may have been a small increase in bioavailability in female subjects weighing >120 kg, although, again, this was not considered clinically relevant.
One potential reason for the limited influence of weight on the pharmacokinetics of rivaroxaban may be its low volume of distribution, as was observed in this study and others.10,16 Rivaroxaban is bound extensively to plasma proteins (
90%)17 and has moderate tissue affinity, with no irreversible binding to any specific organs (in rats).14 These findings support the theory that the distribution of rivaroxaban in humans may be limited mainly to the vascular bed and interstitial space. It is unlikely that factors such as total vascular bed size and total blood volume will vary as significantly between subjects as body weight itself, which is largely affected by the amount of body fat. As rivaroxaban is mainly distributed to these common tissues, its volume of distribution and thus overall exposure may not be affected greatly by body weight, as was observed here.
Rivaroxaban 10 mg had potent pharmacodynamic effects in all weight groups. The maximum inhibition of FXa activity with this dose was similar in the 3 weight groups, whereas the AUC0-tn of inhibition of FXa activity tended to increase with increasing body weight. This could be explained by examining the time course of inhibition of FXa activity, in which FXa activity returned to baseline more quickly in the 50 kg group and more slowly in the >120 kg group. The trend was not significant and is thought to be of little clinical importance.
In contrast to inhibition of FXa, the Emax of PT prolongation was inversely related to body weight (P < .001), with subjects in the 50 kg group having the most pronounced prolongation. AUC0-tn was unaffected possibly because, as for inhibition of FXa activity, the return to baseline was slower with increasing body weight. The pharmacokinetics and pharmacodynamics of rivaroxaban have previously been shown to correlate closely, and there is a particularly strong linear correlation between rivaroxaban plasma concentrations and PT.9,10,16 The increase in the Cmax of rivaroxaban in low-body-weight subjects was therefore probably the cause of the increase in PT Emax in these subjects; however, the 24% increase in Cmax translated to only a 15% increase in PT Emax.
Overall, the effects of extreme body weight on the pharmacokinetics and pharmacodynamics of rivaroxaban in these otherwise healthy subjects were considered small. The AUC of rivaroxaban was increased by 12% to 14% in subjects with both high and low body weight. The Cmax of rivaroxaban was increased slightly, by 24%, in subjects with low body weight but was unaffected in high-body-weight subjects. Differences between the weight groups for the maximum effect of rivaroxaban on inhibition of FXa activity were less than 10%, and differences in AUC0-tn were less than 20%. The maximum effect of rivaroxaban on PT was increased by approximately 15% in low-body-weight subjects and reduced by approximately 18% in high-body-weight subjects; however, the AUC0-tn of PT was influenced by less than 10% by body weight.
Effects of gender on the pharmacokinetics and pharmacodynamics of rivaroxaban were also small. AUC was decreased by about 15% in male subjects of >120 kg and was not affected by gender in the normal-weight group. Cmax was unaffected by gender in normal-weight subjects but was decreased by approximately 19% in high-body-weight male subjects compared with female subjects of the same weight group. For inhibition of FXa activity, the largest difference between the genders was for AUC0-tn, for which there was an increase of 21% in normal-weight female subjects compared with male subjects. Gender affected prolongation of PT by less than 15% in all cases. As a result of these generally small changes due to weight or gender in these healthy subjects (most parameters were affected by less than 15%), it is thought unlikely that dose adjustment of rivaroxaban will be necessary for patients with extremes of body weight or for gender.
Many of the currently available anticoagulants are routinely adjusted for body weight, depending on the indication. Some LMWHs, including enoxaparin and dalteparin, are dosed on a mg/kg basis for the initial treatment of patients with unstable angina/non-Q-wave myocardial infarction18 and also for deep vein thrombosis (DVT) treatment in the case of enoxaparin.19 A recent study has shown that weight-based dosing with dalteparin is a safe option for the treatment of VTE in obese patients.20 Fondaparinux also requires dose adjustment for body weight in DVT treatment. In the pivotal phase 3 trial comparing fondaparinux with enoxaparin in this indication, patients in the <50 kg body weight group (receiving 5 mg fondaparinux) had increased rates of major bleeding compared with patients weighing 50 to 100 kg (3.2% vs 1.2%).1 The effective dose of warfarin should be individually tailored for each patient based on several factors, including not only age21 and ethnicity2 but also body weight2,22 and gender.3 As a result of these restrictions and considerations, an anticoagulant with a fixed dose in each of its indications, irrespective of body weight or gender, would represent a considerable practical and clinical advantage over currently available therapies for prescribing physicians.
In this study, rivaroxaban was as well tolerated in subjects with extremes of body weight as in subjects with normal body weight, and its pharmacokinetics and pharmacodynamics were not influenced by body weight to an extent considered likely to be clinically relevant. The pharmacokinetic and pharmacodynamic effects of rivaroxaban were largely unaffected by gender. Based on these results, it is thought unlikely that dose adjustment of rivaroxaban will be necessary for subjects with extreme body weight or for gender. These findings were confirmed in phase 2 clinical studies of rivaroxaban, in which no dose adjustment was required for any patient, including men or women, or those with extremes of body weight.11-13 However, confirmation of the effect of gender and extreme body weights on the efficacy and safety of rivaroxaban will be required from phase 3 studies in a diverse patient population with significant comorbidities. These studies are ongoing.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Buller HR, Davidson BL, Decousus H, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med. 2004;140: 867-873.
2. Absher RK, Moore ME, Parker MH. Patient-specific factors predictive of warfarin dosage requirements. Ann Pharmacother. 2002; 36: 1512-1517.[Abstract]
3. Garcia D, Regan S, Crowther M, Hughes RA, Hylek EM. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest. 2005;127: 2049-2056.
4. Haslam DW, James WP. Obesity. Lancet. 2005;366: 1197-1209.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. National Institute of Diabetes & Digestive & Kidney Disease. Weight-control information network. Statistics related to overweight and obesity. 2005. Available at: http://win.niddk.nih.gov/statistics/index.htm.
6. Powell A, Teichtahl AJ, Wluka AE, Cicuttini FM. Obesity: a preventable risk factor for large joint osteoarthritis which may act through biomechanical factors. Br J Sports Med. 2005;39: 4-5.
7. Wendelboe AM, Hegmann KT, Biggs JJ, et al. Relationships between body mass indices and surgical replacements of knee and hip joints. Am J Prev Med. 2003;25: 290-295.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126: 429S-456S.
9. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78: 412-421.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61: 873-880.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Turpie AG, Fisher WD, Bauer KA, et al. BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost. 2005;3: 2479-2486.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12. Eriksson BI, Borris L, Dahl OE, et al. Oral, direct factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost. 2006; 4: 121-128.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. Eriksson BI, Borris LC, Dahl OE, et al. A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation. 2006;114: 2374-2381.
14. Weinz C, Buetehorn U, Daehler HP, et al. Pharmacokinetics of BAY 59-7939—an oral, direct factor Xa inhibitor—in rats and dogs. Xenobiotica. 2005;35: 891-910.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
15. US Food and Drug Administration Center for Drug Evaluation and Research. Bioavailability and bioequivalence studies for orally administered drug products—general considerations. 2002. Available at: http://www.fda.gov/cder/guidance/3615fnl.htm.
16. Turpie AGG, Eriksson BI, Mueck W, et al. Pharmacokinetic and pharmacodynamic analyses of rivaroxaban in patients undergoing orthopaedic surgery [abstract]. Pathophysiol Haemost Thromb. 2006;35: A2. Abstract 1182.
17. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban—an oral, direct factor Xa inhibitor—are not affected by aspirin. J Clin Pharmacol. 2006;46: 981-990.
18. Fragmin (dalteparin sodium injection) [prescribing information]. New York, NY: Pfizer; 2004. Available at: http://www.pfizer.com/pfizer/download/uspi_fragmin.pdf.
19. Lovenox (enoxaparin sodium injection) [prescribing information]. Bridgewater, NJ: Sanofi-Aventis; 2005. Available at: http://products.sanofi-aventis.us/lovenox/lovenox.pdf.
20. Al Yaseen E, Wells PS, Anderson J, Martin J, Kovacs MJ. The safety of dosing dalteparin based on actual body weight for the treatment of acute venous thromboembolism in obese patients. J Thromb Haemost. 2005;3: 100-102.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
21. Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med. 2004;141: 745-752.
22. Kamali F, Khan TI, King BP, et al. Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther. 2004;75: 204-212.[CrossRef][Web of Science][Medline]
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