In vitro assessment of the risk of ABCB1-mediated drug–drug interaction between rivaroxaban and tacrolimus in human embryonic kidney 293 recombinant cell lines
Gwenaëlle MahieuAnne‐Laure SennesaelLionel PochetVincent HaufroidFrançoise Van BambekeAnne SpinewineLaure Elens
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BackgroundIn lung transplant patients, direct oral anticoagulants are often taken in combination with immunosuppressive drugs such as tacrolimus. Since tacrolimus is a substrate and inhibitor of the efflux protein ABCB1, also transporting direct oral anticoagulants, a possible drug–drug interaction mediated by competition for this transporter needs to be investigated.ObjectivesTo determine the in vitro effect of tacrolimus on ABCB1-mediated rivaroxaban transport in order to support clinician practice.MethodsRecombinant cell line models, based on human embryonic kidney 293 cells, were generated by a stable transfection process to overexpress ABCB1 or not (control cells). The impact of tacrolimus on ABCB1-mediated rivaroxaban transport was assessed by accumulation experiments.ResultsABCB1 expression decreased the cellular accumulation of rivaroxaban and tacrolimus at their respective clinically relevant concentrations when compared with control cells. This confirms the involvement of ABCB1 in the active transport of tacrolimus and rivaroxaban. However, tacrolimus had no significant influence on rivaroxaban disposition at those clinically relevant concentrations.ConclusionOur study does not provide evidence for a possible interaction between tacrolimus and rivaroxaban when used together in practice.목적: 슬관절 전치환술 후 정맥혈전색전증 예방을 위해 사용하는 Rivaroxaban 또는 Aspirin 사용 후의 혈액학적 변화 및 문제점을 평가하였다. 대상 및 방법: 2010년 7월부터 2011년 3월까지 Rivaroxaban을 사용한 50명과 Aspirin을 사용한 50명의 두 군으로 나누어 혈색소 감소량 및 수혈 빈도의 차이를 비교하였다. 결과: Rivaroxaban군의 평균 혈색소 감소량은 4.7 (3.1-6.6)이었고, Aspirin군은 평균 3.6 (2.0-5.1) 감소되었다(p〈0.05). 혈색소가 8 g/dl 이하로 감소된 경우는 Rivaroxaban군 23명(46%), Aspirin군 9명(18%)이었고 수혈 받은 환자는 Rivaroxaban군 12명(24%), Aspirin군 2명(4%)으로 Rivaroxaban군에서 혈색소 감소량 및 수혈 빈도가 높았으며 통계학적으로 유의한 차이를 보였다(p〈0.05). 결론: Rivaroxaban군에서 Aspirin군보다 실혈량의 증가로 인한 수혈 대상군의 유의한 증가를 보여 표준 정맥혈전색전증 위험도 환자군에서의 Rivaroxaban 사용에 주의가 필요할 것으로 생각된다.
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Background: Rivaroxaban, a direct Xa inhibitor, is one of the new oral antithrombotic agents for which laboratory monitoring is thought to be unnecessary in most cases due to predictable pharmacokinetics. Circumstances are conceivable, however, in which reliable laboratory testing of Rivaroxaban is desirable. The aim of the present in vitro study was to investigate and compare the analytical and practical use of Rivaroxaban monitoring with routine screening assays, thrombin generation and anti-Xa activity, in a clinical laboratory setting.
Thrombin Generation
Prothrombin time
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Several new oral anticoagulants such as rivaroxaban (which targets Factor Xa) and dabigatran etexilate (which targets thrombin) are in advanced stages of clinical development and are already available for clinical use in some countries. Although these agents do not require routine coagulation monitoring, assays to assess the level of anticoagulation may be of assistance in certain circumstances such as in case of overdose, in patients with a hemorrhagic or thromboembolic event during treatment, or to assess compliance. Moreover, the influence of the new oral anticoagulants on routine coagulation tests must be recognized. The prothrombin time is not suitable for rivaroxaban measurement for several reasons, and the routinely used international normalized ratio for monitoring the vitamin K antagonists cannot be applied to rivaroxaban. Development of universal assays is challenging because the new oral anticoagulants have different targets, and even those with the same target have variable effects on routine coagulation assays. Focusing on rivaroxaban, there is emerging evidence that an anti-Factor Xa assay that uses rivaroxaban-containing plasma calibrators may provide the optimal method for determining plasma rivaroxaban concentrations.
Prothrombin complex concentrate
Coagulation testing
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Rivaroxaban is a Direct Oral Anticoagulant (DOAC), which has six licensed indications, including the use for prevention of stroke and systemic embolism with non-valvular Atrial Fibrillation (AF) and the treatment of Venous Thromboembolism (VTE). The pharmacokinetics and the pharmacogenetics of rivaroxaban are reviewed by the author because of a previously reported case of a 43-year-old Caucasian female, who was diagnosed with popliteal and calf Deep Venous Thrombosis (DVT) while on anticoagulation treatment in the form of rivaroxaban 20 mg PO daily. This treatment was started because of a previously verified bilateral Pulmonary Embolism (PE) 5 months earlier. Rivaroxaban is more frequently used in clinical practice, and many physicians are aware that rivaroxaban requires adaptation mainly on the patient's renal function. However, there is still a need to increase awareness of rivaroxaban's interactions with drugs that share its pathways when the hepatic CYP450 and/or P-gp/BCRP are involved. These pathways are utilized by several medications, which are used in cardiovascular and neurological diseases, and the treatment of infections. These interactions can result in under or overexposure to rivaroxaban, which both effects can be detrimental. The author makes several cautious suggestions to decrease the incidence of under/overexposure of rivaroxaban. Physicians, including primary care physicians, could receive a clinical course focusing on DOACs for anticoagulation treatment or direct clinical training within a short-term Anticoagulation Team (ACT) stewardship program concerning adequate prescriptions of rivaroxaban/DOAC as well as their interactions. Also, patients who are elderly and/or with polypharmacy while taking rivaroxaban require more frequent controls. Furthermore, research exploring the effects of ABCG1, ABCG2, CYP3A4, CYP3A5, and Drug-Drug Interactions (DDI), is warranted. Finally, there is a need to identify a validated method for measuring rivaroxaban in primary care.
Apixaban
Stroke
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The main treatment for Antiphospholipid syndrome (APS) is long-term anticoagulation with an oral vitamin K antagonist, although these are associated with numerous problems. Rivaroxaban is a direct anti-factor Xa inhibitor, with a predictable anti-coagulant effect at fixed doses. There are limited reports of rivaroxaban use in APS. We present four cases of patients with APS who received rivaroxaban treatment for six months without thrombosis recurrence or bleeding. Three of the patients received rivaroxaban as initial therapy. In the systematic review, only five patients were treated with rivaroxaban as a thromboprophylaxis. Of the 71 cases of rivaroxaban use including our study, there were seven cases (9.9%) of thrombosis recurrence and two reports of bleeding. The efficacy of rivaroxaban in APS patients was at least equal to warfarin therapy. This report and systematic review suggest that rivaroxaban can be considered cautiously as a thromboprophylactic or alternative therapy for warfarin in patients with APS.
Vitamin K antagonist
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There are several novel anticoagulants in development that target factor Xa(FXa)-the pivotal point of the coagulation cascade. One promising agent is rivaroxaban (a highly selective, oral, direct FXa inhibitor), which is in advanced clinical development for the prevention and treatment of thromboembolic disorders. Oral rivaroxaban may be given in fixed once-daily doses, with the potential for no coagulation monitoring. These properties, along with results from preclinical and clinical studies, suggest that rivaroxaban may have advantages over current treatments. Studies in arterial and venous animal models demonstrated that rivaroxaban has potent antithrombotic effects, without prolonging bleeding times. In healthy subjects, rivaroxaban was well tolerated, with a predictable pharmacological profile and a low propensity for clinically relevant drug-drug interactions. Phase II studies of rivaroxaban for the prevention of venous thromboembolism (VTE) after major orthopedic surgery support these findings. The results also suggested that a total daily dose range of 5 to 20 mg rivaroxaban had similar efficacy and safety to enoxaparin, and that 10 mg rivaroxaban once daily was the optimal dose. This review assesses the preclinical and clinical characteristics of rivaroxaban, and discusses phase II findings with rivaroxaban for the prevention of VTE after major orthopedic surgery.
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Summary Rivaroxaban is a direct factor Xa inhibitor, which can be monitored by anti-factor Xa chromogenic assays. This ex vivo study evaluated different assays for accurate determination of rivaroxaban levels. Eighty plasma samples from patients receiving rivaroxaban (Xarelto®) 10 mg once daily and 20 plasma samples from healthy volunteers were investigated using one anti-factor Xa assay with the addition of exogenous antithrombin and two assays without the addition of antithrombin. Two different lyophilised rivaroxaban calibration sets were used for each assay (low concentration set: 0, 14.5, 59.6 and 97.1 ng/ml; high concentration set: 0, 48.3, 101.3, 194.2 and 433.3 ng/ml). Using a blinded study design, the rivaroxaban concentrations determined by the assays were compared with concentrations measured by HPLC-MS/MS. All assays showed a linear relationship between the rivaroxaban concentrations measured by HPLC-MS/MS and the optical density of the anti-FXa assays. However, the assay with the addition of exogenous anti-thrombin detected falsely high concentrations of rivaroxaban even in plasma samples from controls who had not taken rivaroxaban (intercept values using the high calibrator set and the low calibrator set: +26.49 ng/ml and +13.71 ng/ml, respectively). Plasma samples, initially determined by the high calibrator setting and containing rivaroxaban concentrations <25 ng/ml, had to be re-run using the low calibrator setting for precise measurement. In conclusion, anti-factor Xa chromogenic assays that use rivaroxaban calibrators at different concentration levels can be used to measure accurately a wide range of rivaroxaban concentrations ex vivo. Assays including exogenous antithrombin are unsuitable for measurement of rivaroxaban.
Chromogenic
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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.
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Rivaroxaban, a non-vitamin K antagonist oral anticoagulant, is a potent inhibitor of factor-Xa activity. As a direct oral anticoagulant (DOAC), it is commonly utilized for stroke prevention in patients with non-valvular atrial fibrillation, aiming to decrease the incidence of stroke and systemic embolism.1 The pharmacodynamics of rivaroxaban exhibit predictability irrespective of ethnic variations and demonstrate a robust linear correlation with plasma concentration, with no clinically significant gender-based differences observed.2, 3 Rivaroxaban monotherapy is preferred over combination therapy with antiplatelet agents in the management of cardiovascular disease and major bleeding events.4 While rivaroxaban demonstrates remarkable treatment efficacy, its clinical adoption requires caution. In a comparative study between rivaroxaban and apixaban, rivaroxaban therapy was associated with an increased risk of major ischemic or hemorrhagic events, particularly in elderly patients.5 Conversely, apixaban exhibited a lower incidence of both ischemic stroke or systemic embolism and bleeding in adults diagnosed with atrial fibrillation.6 Attention should be given to the potential side effects of rivaroxaban, which encompass both non-hemorrhagic adverse events and bleeding events.7 Non-hemorrhagic adverse events associated with rivaroxaban include regular occurrences of nausea, vomiting, and constipation. Regarding bleeding events, most studies have primarily focused on evaluating the clinical dosage of rivaroxaban. For instance, the off-label use of low-dose rivaroxaban increases vulnerability to ischemic stroke without reducing the risk of intracranial hemorrhage compared to on-label dosing.8 Furthermore, elderly individuals with atrial fibrillation are particularly susceptible to major bleeding events following rivaroxaban treatment, commonly exhibiting impaired renal function. Consequently, this medication is contraindicated in patients with severe kidney impairment and advanced hepatopathy.9, 10 DOACs have been preferred for prescription due to their favorable pharmacokinetics and pharmacodynamics. However, apart from determining the anticoagulant effects, the plasma concentrations of DOACs are also associated with major bleeding events and stroke prevention. Atrial fibrillation patients receiving DOAC treatment and experiencing bleeding complications have shown higher plasma levels of DOACs.11 Furthermore, inter-individual variations in plasma drug levels of DOACs can be attributed to genetic differences and drug interactions.12 Therefore, the identification of novel genetic variants to modify DOAC plasma levels holds promise for the prevention of related bleeding events. Genetic variants, particularly single nucleotide polymorphisms (SNPs), have the potential to modify disease risk and are often associated with various complications. Recent advances in pharmacogenetics have shed light on the intricate relationship between DOACs and genetic polymorphisms.13 For example, specific genotypes of ABCB1 rs3842 and APOB rs13306198 variants have been linked to an increased risk of bleeding events in patients receiving DOACs.14 In addition to ABCB1, emerging risk factors such as AKR7A3 and ABCA6 were observed; however, the role of genetic variations in bleeding events by rivaroxaban treatment remains unclear and has drawn limited attention15-18 (Table 1). In this issue of Clinical and Translational Medicine, the multicenter prospective cohort study focused on genetic polymorphisms, researchers identified 18 SNPs from 14 genes (including COL6A3, NCAM2, MMP3, VCAN, JCAD) as promising biomarkers for understanding the adverse effects of rivaroxaban. These candidate genes were found to influence multiple regulatory factors associated with bleeding events.18 COL6A3 encodes collagen VI, a cell-binding protein that plays a crucial role in the blood coagulation cascade. MARCH1 is a member of the MARCH family of membrane-bound E3 ubiquitin ligases, responsible for the ubiquitination of specific proteins such as major histocompatibility complex class II proteins. PSAP encodes prosaposin, a highly conserved preproprotein that generates four saposins (A, B, C, D), which act as lysosomal hydrolases involved in the breakdown of sphingolipids. JCAD encodes an endothelial intercellular junction protein, while MMP3 encodes proteins belonging to the matrix metalloproteinase family that play a role in the degradation of the extracellular matrix. NCAM2 encodes a type I membrane protein that is a member of the immunoglobulin superfamily and appears to be involved in selective fasciculation and zone-to-zone projection of primary olfactory axons. According to the Genome-wide Association Study Catalog, multiple polymorphisms in these candidate genes have been associated with various phenotypes, including coronary artery disease, large artery stroke, peripheral arterial disease and ischemic stroke. Taking advantage of their abundant presence in genomes, potential functional impact in coding regions and linkage disequilibrium-derived haplotypes, SNPs offer a distinct contribution to seek an instructive biotarget in the occurrence and progression of disease. For example, variant rs8400 has been demonstrated to affect the activity of miR-186-3p, thereby dysregulating ALKBH5 and promoting the progression of neuroblastoma through the ALKBH5-SPP1 axis.19 Therefore, it is advisable to further investigate the molecular mechanisms underlying disease etiology by focusing on informative SNPs. Additionally, the use of polygenic risk scores (PRS) as an alternative approach is available. By computing the weighted effects of relevant genotypes, PRS enables the prediction of individual susceptibility to bleeding events, offering significant implications for preventive strategies. In conclusion, the identification of genetic polymorphisms associated with bleeding events during rivaroxaban treatment provides potential biomarkers for mitigating adverse effects of direct factor Xa inhibitors. Furthermore, these biomarkers may have implications for other oral anticoagulant drugs such as Vitamin K antagonists and direct thrombin inhibitors. This work was supported by the National Natural Science Foundation of China (grant number: 82173593). The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Apixaban
Edoxaban
Stroke
Vitamin K antagonist
Lightheadedness
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