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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Clinical Pharmacology (Dr Kubitza, Dr Mueck, Dr Zuehlsdorf) and the Department of Biometry, Pharmacometry (Dr Becka), Bayer HealthCare AG, Wuppertal, Germany.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Factor Xa inhibitors • aspirin • oral anticoagulants • rivaroxaban • BAY 59-7939
Factor Xa (FXa) is a promising target for novel anticoagulants because it is at the convergence point of the intrinsic and extrinsic clotting pathways and has relatively few major functions outside coagulation.5 Rivaroxaban (BAY 59-7939; Figure 1) is a novel, oral, direct FXa inhibitor currently in clinical development for the prevention and treatment of arterial and venous thromboembolic disorders. Rivaroxaban inhibits thrombogenesis via selective and potent inhibition of FXa activity and does not require cofactors such as antithrombin.6 Results from previous studies in healthy human subjects have shown that rivaroxaban exerts predictable, dose-dependent anticoagulant effects over a dose range of 5 to 80 mg, is well tolerated with no clinically relevant effect on bleeding time, and has predictable dose-proportional pharmacokinetics.7,8 The results of recent clinical trials of rivaroxaban for the prevention of venous thromboembolism after major orthopedic surgery showed that rivaroxaban has a wide therapeutic window, with similar safety and efficacy to the low molecular weight heparin enoxaparin at doses of 2.5 to 10 mg twice daily, in this setting.9,10 Findings from a further phase II trial in patients undergoing hip replacement surgery confirmed that rivaroxaban 10 mg once daily was the optimum dose for venous thromboembolism prevention in these patients.11 As an oral anticoagulant that is unlikely to require coagulation monitoring because of its predictable pharmacodynamics, rivaroxaban has the potential for long-term administration for the prevention of chronic cardiovascular disorders, such as atrial fibrillation and acute coronary syndromes.
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Aspirin (acetylsalicylic acid) is one of the most widely used medications in the world, with analgesic and anti-inflammatory effects.12 It is a potent antiplatelet agent that strongly and irreversibly inhibits platelet aggregation through inhibition of cyclo-oxygenase 1.12 Numerous clinical trials have shown the efficacy of aspirin for the prevention of occlusive vascular events13; therefore, guidelines recommend it for the prevention and treatment of a number of cardiovascular diseases, including stroke prevention in atrial fibrillation and prevention of myocardial infarction.2,3 Aspirin is readily available without prescription, and patients commonly self-medicate for its anti-inflammatory and analgesic properties; therefore, physicians may be unaware that their patients are taking aspirin. Given the potential clinical indications of rivaroxaban, patients receiving it, either for short-term prevention or treatment of venous thromboembolism or longer term in patients with chronic cardiovascular disorders, will probably also take aspirin at some point. This study was conducted to assess whether aspirin had any effect on the safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban, and vice versa.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Study Design and Treatments
This randomized, nonblinded, 2-way crossover study, with an aspirin run-in period, was approved by the Ethics Committee of the North-Rhine Medical Council, Düsseldorf, Germany, and was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guidelines, and German drug law. The study was conducted at the Institute of Clinical Pharmacology, Bayer HealthCare AG, Wuppertal, Germany.
Subjects were assessed for suitability at a screening visit and were then enrolled into the study. All subjects underwent an aspirin run-in period (Bayer HealthCare AG, Wuppertal, Germany; treatment A) before being randomized to treatment with rivaroxaban alone (Bayer HealthCare AG; treatment B), or rivaroxaban and aspirin (treatment C). Subjects entered the phase I unit on the evening before drug administration. Treatment A comprised aspirin 500 mg on the first day, followed by aspirin 100 mg on the second day; subjects were discharged on the third day. Treatment B comprised rivaroxaban 15 mg on the first day; subjects were discharged on the third day. Treatment C was aspirin 500 mg on the first day, followed by aspirin 100 mg and rivaroxaban 15 mg on the second day; subjects were dis-charged on the fifth day. Subjects who received treatment B first were crossed over to receive treatment C, and vice versa. There were 14-day washout periods between the treatments to allow complete recovery of platelet function, and subjects returned for a final examination approximately 7 days after the last treatment (Figure 2). All treatments were given with water to fasted subjects.
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Aspirin is an irreversible platelet inhibitor,14 and affected platelets remain in circulation for up to 10 days, until they are replaced by natural turnover. The aspirin loading dose of 500 mg chosen for this study should cause complete platelet inhibition, and the 100-mg dose administered on the second day should inhibit platelets introduced into the system in the intervening period. Furthermore, aspirin doses of 500 mg and 100 mg are within the dose range recommended by the guidelines for use in patients with a variety of relevant conditions, including atrial fibrillation, stroke, and acute coronary syndromes.2,3,14-16 Rivaroxaban has been shown to have relevant pharmacodynamic effects at doses between 5 mg and 80 mg7,8; as a result, rivaroxaban 15 mg was chosen as a suitable dose for this study. Subsequently, total daily doses of rivaroxaban between 5 and 20 mg have been shown to be clinically effective in phase II trials.9-11
Assessments
Safety and tolerability. Subjective tolerability of the treatments was assessed by asking the subjects non-leading questions about the occurrence of any adverse event or by spontaneous reporting of adverse events by subjects. Objective tolerability was measured by monitoring the following: hematologic parameters; clinical chemistry; heart rate and blood pressure of subjects in a supine position; and electrocardiogram (ECG) parameters recorded after a resting period of 15 minutes. All assessments were made at least once a day while subjects were in the trial unit; heart rate, blood pressure, and ECG were measured more frequently on days of study drug administration.
Pharmacodynamic parameters. The effects of rivaroxaban and aspirin on FXa activity, prothrombin time (PT), activated partial thromboplastin time (aPTT), and HepTest were assessed before and at regular intervals after study drug administration. Plasma samples were obtained by centrifugation, frozen, and stored below –15°C until analysis. FXa activity was determined by a photometric assay using a 2-step process: Factor X in plasma was activated using Russell's viper venom in the presence of calcium ions; the chromogenic substrate ZD-Arg-Gly-Arg-pNA (S-2765; 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 (NIBSC, Potters Bar, United Kingdom). Concentrations were determined with a precision of 9.5% to 14% and an accuracy of 99.5% to 114% above 0.1 IU/mL (the lower limit of quantification). 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). PT, aPTT, and HepTest (Haemachem, St Louis, Mo) were measured using a ball coagulometer KC 10 (Amelung, Germany), according to the manufacturer's instructions.
Platelet aggregation was analyzed before and 4 hours after study drug administration and was determined quantitatively using the Born method of turbidimetry.17 Platelet-rich plasma was prepared by low-speed centrifugation, and aggregation was induced with a range of collagen concentrations (0.025-1 µg/mL) (Nycomed, Unterschleissheim, Germany). Inhibition of platelet aggregation was calculated by using the first collagen concentration showing maximum aggregation before study drug administration as the 100% aggregation baseline.
Bleeding time was measured before and 4 hours after study drug administration and before discharge, using the Surgicutt device (International Technidyne Corporation, Milan, Italy) following the protocol previously described by Mielke.18
Pharmacokinetic parameters. Blood samples for analysis of the pharmacokinetic parameters of rivaroxaban were taken at the time of rivaroxaban administration and again after 0.5, 1, 2, 3, 4, 6, 8, 12, 15, and 24 hours. Samples were analyzed by a fully validated high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) method (Hewlett-Packard system 1100 coupled with tandem mass spectrometry API 3000; MDS Sciex) after solidphase extraction of rivaroxaban and the internal standard from the matrix using C18 cartridges. A close chemical analogue of rivaroxaban was used as an internal standard.19 Monitored ions were 436 
145 (rivaroxaban) and 464 145 (internal standard). The concentrations were validated by assaying quality control samples of blank plasma spiked with known concentrations of rivaroxaban (n = 18). Concentrations above the lower limit of quantification (0.5 µg/L) were determined with a precision of 3.70% to 8.69% and an accuracy of 96.5% to 101%. Parameters analyzed included area under the plasma concentration–time curve (AUC); AUC normalized to dose and body weight (AUCnorm); maximum plasma concentration (Cmax); Cmax normalized to dose and body weight (Cmax,norm); half-life associated with the terminal slope (t
); time to reach maximum drug concentration in plasma (tmax); and the rivaroxaban fraction unbound (fu) with and without aspirin comedication 2 hours after dosing.
Statistical analyses. The bleeding times and collagen-activated platelet aggregation results for each subject 4 hours after drug administration were analyzed using descriptive statistics. Student paired t tests were used to compare treatments for these pharmacodynamic parameters in a descriptive manner, and 95% confidence intervals (CIs) for the differences were calculated. The pharmacokinetic parameters AUC and Cmax were analyzed by analysis of variance (ANOVA) assuming log-normally distributed data; least squares means and the subsequent ratios of least squares means with 90% CI were then calculated.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Safety and Tolerability
Sixteen treatment-emergent adverse events were reported by 1, 7, and 5 subjects after aspirin alone, rivaroxaban alone, and the combination of rivaroxaban and aspirin, respectively. Of these events, 14 were mild in intensity, 2 were moderate in intensity, and all were resolved by the end of the trial. Moderate-intensity events, which were not considered to be related to study drug, were vertebral disc prolapse causing withdrawal from the trial and lumbago 7 days after the last dose of study medication in the final treatment period (rivaroxaban and aspirin).
Treatment-emergent adverse events that were judged to be possibly related to rivaroxaban were mild headaches after rivaroxaban alone (1 occurrence) and the combination of rivaroxaban and aspirin (1 occurrence), and 4 cases of mild hematoma of the elbow in 3 subjects. Hematomas were observed in 2 subjects after rivaroxaban alone, and 1 subject had 2 hematomas after the combination of rivaroxaban and aspirin. The hematomas were treated with heparin ointment/gel in 2 subjects (30 000 IU); however, this did not affect inhibition of FXa activity, PT, aPTT, or HepTest. Overall, the occurrence and size of hematomas were in line with those observed in other phase I studies investigating nonanticoagulant drugs. Other adverse events reported that were judged not to be related to study medication were tonsillitis in 1 subject after aspirin alone, nasopharyngitis in 1 subject after rivaroxaban alone and 1 subject after the combination of rivaroxaban and aspirin, throat irritation in 2 subjects after rivaroxaban alone, headache and dizziness in 1 subject after rivaroxaban alone, and a dermal cyst in 1 subject after the combination of rivaroxaban and aspirin.
There were no relevant increases in laboratory values after administration of aspirin alone. Increased levels of serum creatine kinase (3.82 x upper limit of normal [ULN]) were observed in 1 subject 1 day after administration of rivaroxaban alone. Levels decreased (2.39 x ULN) on the following day and had normalized by the final examination. The subject experienced a mild hematoma at the same time as the increase in creatine kinase levels; therefore, the increase may be a result of the injury. Increases in glutamate dehydrogenase (maximum 3.08 x ULN) and alanine aminotransferase (maximum 1.90 x ULN) were observed in 2 subjects after administration of the combination of rivaroxaban and aspirin. All values were within normal limits by the final examination. Rivaroxaban alone and aspirin alone had no relevant effect on heart rate or blood pressure, and all ECGs were normal throughout the study.
Pharmacodynamics
FXa activity was inhibited after administration of rivaroxaban alone and in combination with aspirin; aspirin alone had no effect on FXa activity (Figure 3A). Rivaroxaban alone inhibited FXa activity to a maximum level of 34.5% after 3 hours. With the combination of rivaroxaban and aspirin, maximum inhibition (33.0%) was observed after 1 hour. Inhibition of FXa activity returned almost to baseline after 24 hours.
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Aspirin alone and in combination with rivaroxaban inhibited collagen-stimulated platelet aggregation, whereas rivaroxaban alone did not (mean inhibition of aggregation: 86.5%, 98.2%, and –8.4%, respectively; Figure 4). Inhibition of platelet aggregation with aspirin alone was 89.3% greater than with rivaroxaban alone 4 hours after drug administration (Table I). Similarly, inhibition of platelet aggregation was 97.4% greater with the combination of rivaroxaban and aspirin than with rivaroxaban alone. The coadministration of rivaroxaban with aspirin did not significantly affect the inhibitory effect of aspirin on platelet aggregation (P = .055).
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Rivaroxaban alone did not affect bleeding time (Figure 5). In contrast, mean bleeding time was prolonged by 1.46 times baseline and 1.96 times baseline with aspirin and the combination of rivaroxaban and aspirin, respectively. Individual differences showed that bleeding time was significantly prolonged with aspirin alone and the combination of rivaroxaban and aspirin, compared with rivaroxaban alone (Table I; both P < .0001). The combination of rivaroxaban and aspirin prolonged bleeding time slightly more than aspirin alone.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The effects of a 15-mg dose of rivaroxaban on clotting parameters—inhibition of FXa activity, and prolongation of PT, aPTT, and HepTest—were unaffected by coadministration of a loading dose of aspirin at 500 mg followed by a maintenance dose of 100 mg. Therefore, there should be no potentiation of this anticoagulant effect of rivaroxaban when taken concomitantly with aspirin. Furthermore, as PT was unaffected by aspirin coadministration, this commonly available coagulation test could be used to monitor the effects of rivaroxaban, if necessary.
Rivaroxaban had no inhibitory effect on platelet aggregation. The small increase in aggregation observed was within the limits of variability of 10% to 20% reported previously using similar assays.20,21 This is the first time a lack of an effect on platelet aggregation with rivaroxaban has been demonstrated in human subjects and confirms observations made in vitro in human platelet-rich plasma22 and ex vivo using primate blood.23 Coadministration of rivaroxaban with aspirin did not significantly influence the inhibitory effect of aspirin on platelet aggregation, suggesting that rivaroxaban does not affect the anti-platelet activities of aspirin. This lack of effect of rivaroxaban on the antiplatelet properties of aspirin shows that platelet aggregation tests could be used to monitor the effects of aspirin in patients, if necessary, with no concern about concomitant rivaroxaban usage.
Rivaroxaban alone did not affect bleeding time, as has been observed previously,8 whereas aspirin administered alone increased bleeding time, as expected.24 When rivaroxaban and aspirin were given concomitantly, bleeding time was increased compared with aspirin alone; however, although statistically significant (P = .0097), the difference between the treatments was small (mean difference, 2.28 minutes). Bleeding time is highly variable between subjects,25,26 and even large changes in bleeding time may not be predictive of bleeding risk.27 As there was no increased effect on platelet aggregation with coadministration of rivaroxaban and aspirin, compared with aspirin alone, the small increase in bleeding time was not considered to be clinically relevant. These findings suggest that patients receiving rivaroxaban should not be at an increased risk of bleeding during concomitant aspirin therapy, although this will have to be verified by large-scale studies in appropriate patient populations.
The 100-mg aspirin dose had no effect on the predictable pharmacokinetics of rivaroxaban, including no influence on the fu of rivaroxaban in the plasma. Ratios of the AUC and Cmax for rivaroxaban alone and rivaroxaban with aspirin were close to 1, with 90% CIs within the range of 0.8 to 1.25, which is generally accepted as an indication that there is no interaction between 2 drugs.28 Aspirin given concomitantly with rivaroxaban should therefore not affect the absorption, distribution, or excretion of rivaroxaban.
Other phase I studies examining the influence of aspirin on the pharmacodynamics and pharmacokinetics of the indirect FXa inhibitor fondaparinux29 or the direct thrombin inhibitor ximelagatran30 have shown similar results to those presented here. The results of these studies showed that concomitant administration of aspirin had no effect on either the pharmacodynamics or the pharmacokinetics of the anticoagulant. Results for bleeding time in both studies were similar to those presented in this study; an increase in bleeding time occurred with concomitant anticoagulant and aspirin administration compared with the anticoagulant alone or aspirin alone. Both studies concluded that there was no clinically relevant interaction between the anticoagulant and aspirin.29,30 Fondaparinux is now licensed for venous thromboembolism prevention after orthopedic surgery without any restrictions on concomitant aspirin use; ximelagatran was withdrawn from the market because of other safety concerns.
Aspirin is used by many millions of patients worldwide as an analgesic and/or anti-inflammatory agent and for long-term use in patients with a variety of chronic cardiovascular disorders, such as atrial fibrillation and stroke and in acute coronary syndromes.2,3,14-16 Short-term use of rivaroxaban is being investigated for the prevention of venous thromboembolism after major orthopedic surgery, in which it compared favorably with the low molecular weight heparin enoxaparin in recent phase II trials at doses of 2.5 to 10 mg twice daily.9,10 A subsequent trial in patients undergoing hip replacement surgery demonstrated that rivaroxaban 10 mg once daily was the optimum dose for venous thromboembolism prevention in this setting.11 Many patients undergoing orthopedic surgery, especially elective hip and knee replacement, are elderly and may also self-medicate with aspirin for pain relief or its anti-inflammatory properties. These patients may also be taking aspirin chronically, on the advice of their physician, for the management of cardiovascular disorders. Rivaroxaban could also potentially be used long-term in patients with these same chronic cardiovascular disorders. In some cases, it may be necessary for patients to receive an anticoagulant and an antiplatelet agent; concomitant administration of warfarin and aspirin has been associated with a decrease in myocardial infarction and ischemic stroke in patients with acute coronary syndromes compared with aspirin alone but is associated with an increase in major bleeding.31 Rivaroxaban may be a useful alternative to warfarin in these patients, and this will be investigated in future clinical trials. A dose-finding study comparing the oral, direct thrombin inhibitor dabigatran (with or without aspirin) with warfarin for the prevention of thrombotic events in patients with atrial fibrillation found that the risk of bleeding substantially increased in patients receiving concomitant aspirin.32 This finding suggests that this interaction may be a limiting factor for dabigatran in this indication, at least with the dosing regimens tested, and will need to be investigated further. Large-scale clinical trials are required to examine the efficacy of rivaroxaban in chronic cardiovascular disorders and to confirm the absence of clinically relevant bleeding with concomitant administration of rivaroxaban and aspirin observed in this study.
In conclusion, this study with doses of aspirin in the range of those prescribed chronically, and a pharmacologically effective dose of rivaroxaban, showed no clinically relevant interaction between rivaroxaban and aspirin. This will need to be confirmed in future clinical trials. Furthermore, the potential of rivaroxaban as an oral anticoagulant in chronic cardiovascular conditions should be studied in large-scale clinical trials.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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