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1.
High Blood Press Cardiovasc Prev ; 26(5): 413-420, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31617197

RESUMO

INTRODUCTION: Population ageing in developed countries will inevitably increase the need for knee and hip replacement surgery. Over the years, direct oral anticoagulants, such as rivaroxaban, have been widely used for thromboprophylaxis in patients undergoing knee and hip replacement surgery. The study of pharmacogenetic characteristics of rivaroxaban is important for enhancing the effectiveness and safety of rivaroxaban thromboprophylaxis. AIM: Evaluation of CYP3A4, CYP3A5 and ABCB1 gene polymorphisms influence on rivaroxaban pharmacokinetics and prothrombin time dynamics in patients undergoing total hip and knee replacement surgery. METHODS: The study included 78 patients undergoing total hip and knee replacement surgery. The patients received 10 mg of rivaroxaban once a day. Genotyping of polymorphisms ABCB1 rs1045642, ABCB1 rs4148738, CYP3A4 rs35599367 and CYP3A5 rs776746 was performed. Peak steady-state and trough steady-state rivaroxaban concentrations were determined. Prothrombin time was also evaluated. RESULTS: The study revealed the following haplotypes: (1) ABCB1 rs1045642-CYP3A4 rs35599367 and (2) ABCB1 rs4148738-CYP3A4 rs35599367. The analysis of the peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes revealed no significant differences. However, there was a statistically significant average correlation between peak steady-state rivaroxaban concentration and prothrombin time (r = 0.421; r2 = 0.178; p < 0.001). CONCLUSION: No significant difference was identified in peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes. The revealed statistically significant average correlation between the prothrombin time and peak steady-state rivaroxaban concentration is important in clinical practice for assessing the anticoagulant activity of rivaroxaban.


Assuntos
Artroplastia de Quadril , Artroplastia do Joelho , Citocromo P-450 CYP3A/genética , Inibidores do Fator Xa/farmacocinética , Variantes Farmacogenômicos/genética , Rivaroxabana/farmacocinética , Trombose/prevenção & controle , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Idoso , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Citocromo P-450 CYP3A/metabolismo , Monitoramento de Medicamentos/métodos , Inibidores do Fator Xa/administração & dosagem , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Protrombina , Rivaroxabana/administração & dosagem , Trombose/etiologia , Resultado do Tratamento
3.
Lancet Haematol ; 6(10): e500-e509, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31420317

RESUMO

BACKGROUND: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. METHODS: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. FINDINGS: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2-10·6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0-3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events. INTERPRETATION: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism. FUNDING: Bayer AG, Janssen Research and Development.


Assuntos
Anticoagulantes/uso terapêutico , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Adolescente , Anemia/etiologia , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Peso Corporal , Criança , Pré-Escolar , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Fator Xa/análise , Feminino , Meia-Vida , Hemorragia/etiologia , Humanos , Lactente , Masculino , Neutropenia/etiologia , Tempo de Protrombina , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacocinética , Resultado do Tratamento , Tromboembolia Venosa/patologia
4.
Ther Adv Cardiovasc Dis ; 13: 1753944719863641, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31364490

RESUMO

BACKGROUND: This analysis aimed to evaluate the impact of rivaroxaban exposure and patient characteristics on efficacy and safety outcomes in patients with acute coronary syndrome (ACS) and to determine whether therapeutic drug monitoring might provide additional information regarding rivaroxaban dose, beyond what patient characteristics provide. METHODS: A post hoc exposure-response analysis was conducted using data from the phase III ATLAS ACS 2 Thrombolysis in Myocardial Infarction (TIMI) 51 study, in which 15,526 randomized ACS patients received rivaroxaban (2.5 mg or 5 mg twice daily) or placebo for a mean of 13 months (maximum follow up: 31 months). A multivariate Cox model was used to correlate individual predicted rivaroxaban exposures and patient characteristics with time-to-event clinical outcomes. RESULTS: For the incidence of myocardial infarction (MI), ischemic stroke, or nonhemorrhagic cardiovascular death, hazard ratios (HRs) for steady-state maximum plasma concentration (Cmax) in the 5th and 95th percentiles versus the median were statistically significant but close to 1 for both rivaroxaban doses. For TIMI major bleeding events, a statistically significant association was observed with Cmax [HR, 1.08; 95% CI, 1.06-1.11 (95th percentile versus median, 2.5 mg twice daily)], sex [HR, 0.56; 95% CI, 0.38-0.84 (female versus male)], and previous revascularization [HR, 0.62; 95% CI, 0.44-0.87 (no versus yes)]. CONCLUSIONS: The shallow slopes of the exposure-response relationships and the lack of a clear therapeutic window render it unlikely that therapeutic drug monitoring in patients with ACS would provide additional information regarding rivaroxaban dose beyond that provided by patient characteristics.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Modelos Biológicos , Rivaroxabana/administração & dosagem , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/mortalidade , Idoso , Isquemia Encefálica/mortalidade , Tomada de Decisão Clínica , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/farmacocinética , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacocinética , Acidente Vascular Cerebral/mortalidade , Resultado do Tratamento
5.
Am J Health Syst Pharm ; 76(8): 505-511, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-31361865

RESUMO

PURPOSE: This case series presents 3 patients with acute kidney injury taking apixaban or rivaroxaban and transitioning to a heparin infusion. SUMMARY: Case 1 was a 78-year-old man admitted with respiratory failure, acute decompensated heart failure, and acute kidney injury. He was taking apixaban for atrial flutter. He was transitioned to an i.v. heparin infusion and had 2 consecutive heparin antifactor-Xa levels greater than 2 units/mL. Heparin was held and resumed about 36 hours later when the apixaban anti-Xa level was less than 50 ng/mL. Case 2 was a 55-year-old man admitted with acute kidney injury, taking apixaban for a recent deep vein thrombosis. Apixaban anti-Xa levels were monitored and i.v. heparin was initiated when the level was less than 100 ng/mL, about 56 hours after the last apixaban dose. Case 3 was a 64-year-old woman admitted with sepsis and acute kidney injury taking rivaroxaban for pulmonary embolism, which occurred 2 weeks prior to admission. Rivaroxaban anti-Xa levels were monitored and i.v. heparin was initiated about 36 hours after the last dose when the level was less than 100 ng/mL. The management strategy did not lead to any thrombotic outcomes; however, 1 patient experienced bleeding. CONCLUSION: Specific anti-Xa levels for rivaroxaban and apixaban appeared to be helpful in the transition of 3 patients to unfractionated heparin infusions in the setting of acute kidney injury. These levels provided enhanced, individualized care and likely helped avoid over and under anticoagulation.


Assuntos
Lesão Renal Aguda/fisiopatologia , Monitoramento de Medicamentos , Inibidores do Fator Xa/análise , Heparina/análise , Pirazóis/análise , Piridonas/análise , Administração Oral , Idoso , Flutter Atrial/tratamento farmacológico , Substituição de Medicamentos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Feminino , Heparina/administração & dosagem , Humanos , Infusões Intravenosas , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/tratamento farmacológico , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Piridonas/administração & dosagem , Piridonas/farmacocinética , Eliminação Renal , Rivaroxabana/administração & dosagem , Rivaroxabana/análise , Rivaroxabana/farmacocinética , Trombose Venosa/tratamento farmacológico
6.
Artigo em Inglês | MEDLINE | ID: mdl-31055191

RESUMO

A Micellar Chromatographic method to determine rivaroxaban in plasma and urine has been developed. The samples were dissolved in the mobile phase (SDS 0.05 M - 1-propanol 12.5%, phosphate buffered at pH 7) and 20 µL directly injected, avoiding the extraction and purification steps. Using a C18 column and running under isocratic mode at 1 mL/min, analyte was eluted without interference from the matrix in <6.0 min. The detection absorbance wavelength was set to 250 nm. The procedure was validated by Food and Drug Administration guidelines in terms of: system suitability, calibration range (0.05-5 mg/L), linearity, sensitivity, robustness, carry-over effect, specificity, accuracy (-11.1 to 4.2%), precision (<19.9%), stability and analysis of incurred samples. The method was found reliable, practical, easy-to-conduct, rapid, relatively eco-friendly, safe, inexpensive, widely available and with a high sample throughput. The method was applied to the analysis of incurred samples, including incurred sample reanalysis, to verify that the instrumentation works correctly. In addition, the constants of the different partition equilibria occurring in the column were elucidated in order to have a better comprehension of the theoretical aspects of the retention mechanism. A moderately strong association between rivaroxaban and the stationary phase and the micelles was found, weakened by short chain alcohol.


Assuntos
Cromatografia Líquida/métodos , Rivaroxabana/sangue , Rivaroxabana/urina , Humanos , Limite de Detecção , Modelos Lineares , Micelas , Reprodutibilidade dos Testes , Rivaroxabana/farmacocinética
7.
Clin Appl Thromb Hemost ; 25: 1076029619847524, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31088146

RESUMO

The currently available oral anti-Xa agents are claimed to produce their anticoagulant and antithrombotic effects solely by the inhibition of factor Xa. This study profiled various anti-Xa drugs in routinely used laboratory assays to demonstrate that their effects are not solely related to the anti-Xa activities. Apixaban, betrixaban, edoxaban, and rivaroxaban were obtained commercially. Native and citrated whole blood was used for the activated clotting time (ACT) and thromboelastography (TEG). Citrated plasma was used for monitoring the prothrombin time (PT), activated partial thromboplastin time (aPTT), Heptest, and prothrombinase-induced clotting time (PiCT) tests. An amidolytic method was used for the determination of anti-Xa effects. Thrombin-induced fibrinokinetics was monitored optically. Thrombin generation studies were carried out using the calibrated automated thrombogram. All of the anti-Xa agents produced concentration- and assay-dependent effects. In the ACT at 2.5 µg/mL and TEG at 1.0 µg/mL, edoxaban exhibited the strongest anticoagulation effect. In the PiCT, PT, and aPTT assay at 1 µg/mL, edoxaban showed stronger effects than other agents. The half maximal inhibitory concentration of these agents for the inhibition of factor Xa ranged from 340 to >1000 ng/mL. In the thrombin generation inhibition assay, apixaban showed the strongest activity. In the fibrinokinetics, different anti-Xa agents produced varying degrees of inhibition. These results demonstrate that the measured anti-Xa activity alone does not fully reflect the overall biologic spectrum of these agents.


Assuntos
Benzamidas , Inibidores do Fator Xa , Fator Xa/metabolismo , Tempo de Protrombina , Pirazóis , Piridinas , Piridonas , Rivaroxabana , Benzamidas/farmacocinética , Benzamidas/farmacologia , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/farmacologia , Humanos , Tempo de Tromboplastina Parcial , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Piridonas/farmacocinética , Piridonas/farmacologia , Rivaroxabana/farmacocinética , Rivaroxabana/farmacologia , Tiazóis/farmacocinética , Tiazóis/farmacologia , Tromboelastografia
8.
J Vet Intern Med ; 33(3): 1322-1330, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30859645

RESUMO

BACKGROUND: The chromogenic anti-Xa assay, the gold standard for monitoring the anti-Xa effect of rivaroxaban, is not available as a cage-side diagnostic test for use in a clinical setting. HYPOTHESIS/OBJECTIVES: To evaluate clinical modalities for measuring the anticoagulant effects of rivaroxaban using a point-of-care prothrombin time (PT) and thromboelastography (TEG). ANIMALS: Six healthy Beagle dogs. METHODS: Prospective, experimental study. Four different doses of rivaroxaban (0.5, 1, 2, and 4 mg/kg) were administered PO to dogs. Single PO and 3 consecutive dosing regimens also were assessed. Plasma rivaroxaban concentration was determined using a chromogenic anti-Xa assay, point-of-care PT, and TEG analysis with 4 activators (RapidTEG, 1 : 100 tissue factor [TF100], 1 : 3700 tissue factor [TF3700], and kaolin), and results were compared. Spearman correlation coefficients were calculated between ratios (peak to baseline PT; peak reaction time [R] of TEG to baseline [R] of TEG) and anti-Xa concentration. RESULTS: Anti-Xa concentration had a significant correlation with point-of-care PT (R = 0.82, P < .001) and RapidTEG-TEG, TF100-TEG, and TF3700-TEG (R = 0.76, P < .001; R = 0.82, P < .001; and R = 0.83, P < .001, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Overall, a 1.5-1.9 × delay in PT and R values of TEG 3 hours after rivaroxaban administration is required to achieve therapeutic anti-Xa concentrations of rivaroxaban in canine plasma. The R values of TEG, specifically using tissue factors (RapidTEG, TF100, TF3700) and point-of-care PT for rivaroxaban can be used practically for therapeutic monitoring of rivaroxaban in dogs.


Assuntos
Inibidores do Fator Xa/farmacologia , Tempo de Protrombina/veterinária , Rivaroxabana/farmacologia , Tromboelastografia/veterinária , Animais , Cães/sangue , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Masculino , Estudos Prospectivos , Rivaroxabana/administração & dosagem , Rivaroxabana/farmacocinética
9.
Eur J Clin Pharmacol ; 75(6): 817-824, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30725221

RESUMO

PURPOSE: Rivaroxaban is a substrate for ABCB1 transporter and is commonly used in patients undergoing hip or knee replacement surgery for thromboprophylaxis. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model to investigate the influence of ABCB1 gene expression and polymorphism on rivaroxaban exposure and anticoagulation effects. METHODS: Five blood samples per patient were collected during 5 days after the surgery for the determination of rivaroxaban concentration in plasma and for determination of prothrombin time and partial thromboplastin time. Non-linear mixed effects model was used for a population PK-PD analysis and for testing covariate effects. RESULTS: A one-compartment PK model with first-order absorption adequately described the pharmacokinetic data. The typical oral clearance (CL/F) was 6.12 L/h (relative standard error, 15.8%) and was associated with ABCB1 expression. Compared to base line before the surgery, a significant ABCB1 downregulation was observed 5 days after the surgery (p < 0.001). Prothrombin time and partial thromboplastin time were both linearly associated to the logarithm of the rivaroxaban plasma concentration. CONCLUSIONS: We confirmed that variable rivaroxaban CL/F is associated with ABCB1 expression, which is in accordance with previous studies on P-glycoprotein involvement in rivaroxaban PK. Furthermore, we observed the downregulation of ABCB1 expression after the surgery. The cause remains unclear and further research is needed to explain the underlying mechanisms.


Assuntos
Artroplastia de Quadril , Artroplastia do Joelho , Inibidores do Fator Xa/farmacocinética , Modelos Biológicos , Rivaroxabana/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Idoso de 80 Anos ou mais , Regulação para Baixo , Inibidores do Fator Xa/sangue , Inibidores do Fator Xa/uso terapêutico , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Período Pós-Operatório , Rivaroxabana/sangue , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/prevenção & controle
10.
J Liposome Res ; 29(4): 399-412, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30720378

RESUMO

The increasing incidence of venous thromboembolism (VTE) in paediatric population has stimulated the development of liquid anticoagulant formulations. Thus our goal is to formulate a liquid formulation of poorly-water soluble anticoagulant, rivaroxaban (RIVA), for paediatric use and to assess the possibility of its intravenous administration in emergencies. Self-nanoemulsifying drug delivery systems (SNEDDSs) were developed and characterized. SNEDDS constituents were estimated from the saturated solubility study followed by plotting the corresponding ternary phase diagrams to determine the best self-emulsified systems. Thermodynamic stability, emulsification, dispersibility, robustness to dilution tests, in vitro dissolution, particle size, and zeta potential were executed to optimize the formulations. The optimized formulation, that composed of Capryol 90:Tween 20:PEG 300 (5:45:50), increased RIVA solubility (285.7-fold than water), it formed nanoemulsion with a particle size of 16.15 nm, PDI of 0.25 and zeta potential of -21.8. It released 100.83 ± 2.78% of RIVA after 5 min. SNEDDS was robust to dilution with oral and parenteral fluids and showed safety to human RBCs. SNEDDS showed enhanced bioavailability after oral and intravenous administration than the oral drug suspension (by 1.25 and 1.26-fold, respectively). Moreover, it exhibited enhanced anticoagulant efficacy in the prevention and treatment of carrageenan-induced thrombosis rat model.


Assuntos
Anticoagulantes/química , Emulsões/química , Nanocápsulas/química , Rivaroxabana/química , Tromboembolia Venosa/tratamento farmacológico , Animais , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacocinética , Disponibilidade Biológica , Química Farmacêutica , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Emergências , Humanos , Modelos Animais , Tamanho da Partícula , Polietilenoglicóis/química , Polímeros/química , Polissorbatos/química , Propilenoglicóis/química , Ratos , Reologia , Rivaroxabana/administração & dosagem , Rivaroxabana/farmacocinética , Solubilidade , Propriedades de Superfície , Água
11.
Eur J Anaesthesiol ; 36(6): 449-456, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30308522

RESUMO

BACKGROUND: Rapid detection of the anticoagulant effect of oral factor Xa (FXa) inhibitors may be essential in several emergency clinical situations. Specific assays quantifying the drugs are performed in plasma and require a turnaround time that is too long to be useful in emergency situations. Rotational thromboelastometry (ROTEM) is a whole blood coagulation assay of blood viscoelasticity and could be of interest for FXa inhibitor detection in emergency. However, conventional ROTEM reagents only detect high amounts of inhibitors. OBJECTIVE: The aim of this study was first to assess the effect of whole blood components on the viscoelastic measurement of the effects of FXa inhibitors, and second to evaluate whether a modified ROTEM, triggered with a low amount of tissue factor and a saturating amount of phospholipid vesicles, can reliably detect low levels of FXa inhibitor activity in whole blood. DESIGN: Diagnostic test study. SETTINGS: A university research laboratory. From November 2014 to April 2016. PATIENTS: Sixty-six patients: 30 treated with rivaroxaban, 17 with apixaban and 19 without treatment. INTERVENTION: ROTEM was triggered with 2.5 pmol l of tissue factor and 10 µmol l of phospholipid vesicles. MAIN OUTCOME MEASURES: Modified ROTEM parameters were measured in different experimental conditions: platelet-poor plasma (PPP), platelet-rich plasma, PPP supplemented with fibrinogen and reconstituted whole blood with various haematocrit levels adjusted between 30 and 60%. Modified ROTEM was further validated using whole blood from patients who were either treated or not treated with FXa inhibitors. RESULTS: Modified ROTEM allowed detection of as little as 25 ng ml FXa inhibitors in PPP, with at least a 1.4-fold increase of the clotting time (P ≤ 0.02). Neither changes of fibrinogen concentration nor variations of platelet count or haematocrit precluded FXa inhibitor detection. A lengthened modified ROTEM clotting time of more than 197 s allowed detection of FXa inhibitor concentrations above 30 ng ml in whole blood with 90% sensitivity and 85% specificity. CONCLUSION: Modified ROTEM may be applicable in emergency situations for the detection of FXa inhibitors in whole blood.


Assuntos
Inibidores do Fator Xa/sangue , Tromboelastografia/métodos , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Coagulação Sanguínea/efeitos dos fármacos , Cuidados Críticos/métodos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/sangue , Pirazóis/farmacocinética , Piridonas/administração & dosagem , Piridonas/sangue , Piridonas/farmacocinética , Rivaroxabana/administração & dosagem , Rivaroxabana/sangue , Rivaroxabana/farmacocinética , Sensibilidade e Especificidade , Fatores de Tempo , Adulto Jovem
12.
Eur J Drug Metab Pharmacokinet ; 44(2): 229-236, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30151746

RESUMO

BACKGROUND AND OBJECTIVES: There have been no animal experiments and clinical studies on the pharmacokinetic interaction between rivaroxaban and enalapril. To investigate whether a potential pharmacokinetic interaction is present between rivaroxaban and enalapril, a rapid and sensitive Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine the concentration of rivaroxaban and enalapril in rat plasma and was then applied to a pharmacokinetic interaction study. METHODS: The analytes were separated on an Acquity UPLC BEH C18 chromatography column (2.1 × 50 mm, 1.7 µm) with acetonitrile and 0.1% formic acid as the mobile phase with gradient elution. The mass spectrometer was operated in multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of 436.1 → 145.1 m/z for rivaroxaban, 377.3 → 234.2 m/z for enalapril and 285.2 → 193.1 m/z for diazepam (IS). RESULTS: The method was validated over the concentration range of 1.0-200 ng/mL for rivaroxaban and 0.5-100 ng/mL for enalapril. The intra- and inter-day precision and accuracy of the quality control (QC) samples exhibited relative standard deviations (RSD) < 9.4% and the accuracy values ranged from - 8.3 to 9.6%. After co-administration of rivaroxaban and enalapril, the maximum plasma concentration (Cmax) and area under the systemic drug concentration-time curve from time 0 to infinity (AUC0-∞) of rivaroxaban were significantly increased by 19.6% (p < 0.05) and 21.3% (p < 0.05), respectively. On the contrary, the plasma clearance rate (CL/F) of rivaroxaban and enalapril was significantly decreased by 17.8% (p < 0.05) and 23.8% (p < 0.05), respectively. CONCLUSIONS: The UPLC-MS/MS method was successfully applied to simultaneous determination of rivaroxaban and enalapril in rat plasma and applied to study the pharmacokinetic interaction between rivaroxaban and enalapril. The co-administration of rivaroxaban and enalapril resulted in a significant drug interaction in rats.


Assuntos
Enalapril/sangue , Rivaroxabana/sangue , Espectrometria de Massas em Tandem/métodos , Inibidores da Enzima Conversora de Angiotensina/sangue , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão/métodos , Relação Dose-Resposta a Droga , Interações de Medicamentos/fisiologia , Enalapril/farmacocinética , Inibidores do Fator Xa/sangue , Inibidores do Fator Xa/farmacocinética , Masculino , Ratos , Ratos Sprague-Dawley , Rivaroxabana/farmacocinética
13.
Xenobiotica ; 49(9): 1001-1006, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30216091

RESUMO

Steady-state plasma concentrations of anticoagulants and the time since the previous administration in mainly outpatients with atrial fibrillation administered standard or reduced doses were analyzed for 110 elderly Japanese subjects (mean age, 76 years) treated with apixaban (2.5 or 5.0 mg twice daily), dabigatran etexilate (110 or 150 mg twice daily), edoxaban (30 or 60 mg once daily) or rivaroxaban (10 or 15 mg once daily) at one general hospital. The pharmacokinetics in patients treated with standard and reduced doses of the four anticoagulants using liquid chromatography-tandem mass spectrometry was compared with the concentration ranges estimated using physiologically based pharmacokinetic modeling. Reduced doses of anticoagulants resulted in relatively small pharmacokinetic variations compared with the standard dose. Statistical analyses revealed that renal impairment is likely not the sole determinant factor for high plasma concentrations of apixaban, dabigatran, edoxaban and rivaroxaban. Patients with atrial fibrillation should be treated with the correct doses of oral anticoagulants as specified in the package inserts (e.g. reduced doses for elderly patients, patients with low body weights and in combination with P-glycoprotein inhibitor drugs) to avoid excessive or insufficient doses of direct oral anticoagulants.


Assuntos
Anticoagulantes/sangue , Anticoagulantes/farmacocinética , Fibrilação Atrial/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Dabigatrana/administração & dosagem , Dabigatrana/efeitos adversos , Dabigatrana/sangue , Dabigatrana/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Nefropatias/induzido quimicamente , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirazóis/sangue , Pirazóis/farmacocinética , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/sangue , Piridinas/farmacocinética , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Piridonas/sangue , Piridonas/farmacocinética , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Rivaroxabana/sangue , Rivaroxabana/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Tiazóis/sangue , Tiazóis/farmacocinética
14.
Drugs Aging ; 36(1): 65-71, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30411284

RESUMO

BACKGROUND: Use of direct-acting oral anticoagulants (DOACs) is increasing, but knowledge about pharmacokinetics and safety in frail patients is lacking. OBJECTIVE: The aim was to determine serum concentrations and elimination rates of DOACs in older hip fracture patients hospitalized for surgery. METHODS: The study included patients ≥ 65 years of age hospitalized for acute hip fracture surgery over a period of 6 months. Use of antithrombotic drugs was registered and serum samples collected for analysis of DOACs (apixaban, dabigatran and rivaroxaban) at admission and surgery. Measured concentrations were assessed in relation to reference (therapeutic) ranges of the respective drugs and applied for half-life calculations. Furthermore, waiting time for surgery was compared between DOAC and warfarin users. RESULTS: Of 167 patients included (median age 84 years), 11 and 14 used DOACs and warfarin, respectively. Seven of the DOAC-treated patients had concentrations above the upper reference range (> 300 nM) at admission, and concentrations were still in the reference range for five of these at surgery. Elimination half-lives could be estimated in eight patients and ranged between 14.6 and 59.7 h (median 21.6). The observed waiting time for surgery was longer for patients using DOACs than warfarin (median 44 vs. 25 h). CONCLUSION: This pilot study indicates that older patients prone to hip fracture are at risk of being exposed to therapeutic serum concentrations of DOACs during surgery due to reduced drug elimination rates. The observation that almost 50% of the patients had therapeutic concentrations at surgery should be investigated further regarding safety of DOAC use in this frail elderly population.


Assuntos
Anticoagulantes/uso terapêutico , Fraturas do Quadril/cirurgia , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/farmacocinética , Dabigatrana/farmacocinética , Dabigatrana/uso terapêutico , Feminino , Fraturas do Quadril/tratamento farmacológico , Humanos , Masculino , Projetos Piloto , Estudos Prospectivos , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Piridonas/farmacocinética , Piridonas/uso terapêutico , Rivaroxabana/farmacocinética , Rivaroxabana/uso terapêutico , Varfarina/farmacocinética , Varfarina/uso terapêutico
15.
Transfusion ; 58(12): 3014-3026, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30343500

RESUMO

BACKGROUND: Uncontrollable bleeding is the leading cause of death in traumatically injured patients. The extent to which direct factor Xa inhibitors interfere with the applied resuscitation measures is presently unknown. STUDY DESIGN AND METHODS: In this study, we investigated the effect of the resuscitation fluids saline, albumin, fresh frozen plasma (FFP) and solvent/detergent (S/D)-treated plasma, fibrinogen concentrate, prothrombin complex concentrate (PCC), and combinations thereof on the hemostatic profile of rivaroxaban-anticoagulated whole blood and plasma. We used rivaroxaban-spiked whole blood and plasma from healthy donors, as well as plasma from patients on rivaroxaban, and mimicked a resuscitation approach in a 50% plasma dilution setting. Thromboelastography, thrombin generation, and fibrin generation clot lysis test were assessed using tissue factor to initiate coagulation and tissue plasminogen activator to induce clot lysis. RESULTS: Rivaroxaban resulted in a hypocoagulant state that remained largely unaltered upon subsequent 50% dilution with S/D-treated plasma or FFP. Using S/D-treated plasma as a diluent, clot stability decreased due to its low α2 -antiplasmin. Dilution with saline and albumin induced a profibrinolytic state and further deteriorated the impaired hemostatic potential of rivaroxaban-anticoagulated blood, even after PCC and fibrinogen support. Combined use of plasma (either FFP or S/D treated) and PCC, however, considerably improved both coagulation and clot stability. CONCLUSION: In the setting of rivaroxaban anticoagulation and major blood loss, transfusing plasma together with PCC may provide the most effective resuscitation approach with the notion that additional antifibrinolytic drug support (e.g., tranexamic acid) is likely required.


Assuntos
Anticoagulantes , Hemostasia/efeitos dos fármacos , Plasma , Ressuscitação , Rivaroxabana , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Feminino , Humanos , Masculino , Rivaroxabana/farmacocinética , Rivaroxabana/farmacologia
16.
Br J Clin Pharmacol ; 84(12): 2903-2913, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30192025

RESUMO

AIMS: We assessed the potential mutual interaction of oral macitentan (cytochrome P450 (CYP) 3A4 substrate) at steady-state with single-dose oral rivaroxaban (CYP3A4 and P-glycoprotein substrate) and evaluated the effect of the CYP3A and P-glycoprotein inducer St John's wort (SJW) on the pharmacokinetics of these drugs in healthy volunteers. METHODS: Twelve healthy volunteers completed this open-label, monocentre, two-period, one-sequence phase I clinical trial. The pharmacokinetics of macitentan (10 mg) was assessed on study days 3 (single dose), 15 (steady-state), 16 (impact of rivaroxaban) and 29 (after induction by oral SJW), and of rivaroxaban on days 2 (single dose), 16 (impact of macitentan at steady-state) and 29 (after induction by SJW). Concurrently, we quantified changes of CYP3A activity using oral microdoses of midazolam (30 µg). RESULTS: Rivaroxaban and macitentan did not significantly change the pharmacokinetics of each other. After induction with SJW, CYP3A activity increased by 272% and geometric mean ratios of macitentan AUC decreased by 48% and of Cmax by 45%. Concurrently, also geometric mean ratios of rivaroxaban AUC and Cmax decreased by 25%. CONCLUSIONS: There is no evidence for a relevant pharmacokinetic interaction between macitentan and rivaroxaban suggesting that these two drugs can be combined without dose adjustment. SJW strongly increased CYP3A activity and substantially reduced rivaroxaban and macitentan exposure while estimated net endothelin antagonism only decreased by 20%, which is considered clinically irrelevant. The combination of SJW with rivaroxaban should be avoided.


Assuntos
Hypericum , Pirimidinas/administração & dosagem , Rivaroxabana/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Área Sob a Curva , Citocromo P-450 CYP3A/fisiologia , Interações de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Pirimidinas/farmacocinética , Rivaroxabana/farmacocinética , Sulfonamidas/farmacocinética
17.
Sci Rep ; 8(1): 10514, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30002384

RESUMO

Direct oral anticoagulants (DOAC) are substrates for the ABCB1 transporter (also called P-glycoprotein), an active efflux pump. ABCB1 polymorphisms have been previously reported to influence the pharmacokinetics of several drugs such as immunosuppressants and tyrosine kinase inhibitors. Recently, in vivo studies have suggested that genetic variants might contribute to the inter-individual variability in DOAC plasma concentrations. Therefore, we evaluated the in vitro effect of the most common coding ABCB1 single nucleotide polymorphisms (SNP), 1236 C > T-2677G > T-3435C > T, and the coding ABCB1 1199 G > A SNP on the transport activity towards rivaroxaban. HEK293 cells were transfected to overexpress the ABCB1 wild-type (1236C-2677G-3435C, 1199 G) or variant proteins (1236C-2677G-3435T, 1236T-2677T-3435T or 1199 A). ABCB1 expression decreased the intracellular accumulation of rivaroxaban, when compared to control cells. This confirms the involvement of ABCB1 in the active transport of rivaroxaban. However, the ABCB1 1236 C > T-2677G > T-3435C > T and 1199 G > A SNPs had no significant influence on the intracellular accumulation of rivaroxaban when compared to the wild-type protein. These results suggest that the ABCB1 coding SNPs investigated in the present study are unlikely to contribute to the inter-individual variability in rivaroxaban plasma concentrations.


Assuntos
Variação Biológica da População/genética , Rivaroxabana/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Células HEK293 , Humanos , Polimorfismo de Nucleotídeo Único , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transfecção
18.
Molecules ; 23(6)2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29914049

RESUMO

Indobufen is a new generation of anti-platelet aggregation drug, but studies were not sufficient on its anticoagulant effects. In the present study, the anticoagulant activity of indobufen was determined by monitoring the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) in rabbit plasma. We evaluated the anticoagulant mechanisms on the content of the platelet factor 3,4 (PF3,4), and the coagulation factor 1, 2, 5, 8, 10 (FI, II, V, VIII, X) in rabbits, as well as the in vivo bleeding time and clotting time in mice. The pharmacodynamic differences between indobufen and warfarin sodium, rivaroxaban, and dabigatran were further studied on thrombus formation and the content of FII and FX in rats. Animal experiments showed that intragastric-administrated indobufen can significantly reduce the APTT, PT, TT, PF3, FI, II, V, VIII, and X plasma contents. Its inhibitory effect on plasma FII was better than thrombin inhibitor dabigatran with effect on FX better than FXa inhibitor rivaroxaban. These results suggest that indobufen has some anticoagulant effects as strong as some conventional anticoagulants. The mechanism may be related to both exogenous and endogenous coagulation system.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Isoindóis/farmacologia , Fenilbutiratos/farmacologia , Fator Plaquetário 3/metabolismo , Fator Plaquetário 4/metabolismo , Animais , Anticoagulantes/química , Anticoagulantes/farmacocinética , Testes de Coagulação Sanguínea , Dabigatrana/farmacocinética , Feminino , Isoindóis/química , Isoindóis/farmacocinética , Masculino , Estrutura Molecular , Tempo de Tromboplastina Parcial , Fenilbutiratos/química , Fenilbutiratos/farmacocinética , Tempo de Protrombina , Coelhos , Ratos , Rivaroxabana/farmacocinética , Tempo de Trombina
19.
Praxis (Bern 1994) ; 107(13): 683-687, 2018 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-29921184

RESUMO

The Multimorbid Patient: Use of New Oral Anticoagulants in Patients with Chronic Kidney Disease Abstract. Increasing life expectancy in Western countries is associated with a high prevalence of multiple chronic diseases which is defined by the term "multimorbidity". Many of these patients suffer from chronic kidney disease (CKD) and thrombogenic comorbidities such as atrial fibrillation with the need for oral anticoagulation. For decades vitamin K antagonists have been exclusively prescribed for oral anticoagulation. However, due to altered pharmacokinetics and bioavailability of these drugs in CKD, a significant risk of bleeding exists. The introduction of direct oral anticoagulants as a new and promising alternative to vitamin K antagonists was -especially for CKD patients - highly anticipated. However, data from randomized studies are missing for older patients with advanced CKD. Consequently, a careful evaluation of the risk-benefit ratio is recommended for this sensitive patient population.


Assuntos
Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Arteriopatias Oclusivas/tratamento farmacológico , Fibrilação Atrial/tratamento farmacológico , Doença das Coronárias/tratamento farmacológico , Falência Renal Crônica/tratamento farmacológico , Tromboembolia/tratamento farmacológico , Anticoagulantes/farmacocinética , Comorbidade , Contraindicações , Dabigatrana/efeitos adversos , Dabigatrana/farmacocinética , Dabigatrana/uso terapêutico , Taxa de Filtração Glomerular/efeitos dos fármacos , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Piridinas/efeitos adversos , Piridinas/farmacocinética , Piridinas/uso terapêutico , Piridonas/efeitos adversos , Piridonas/farmacocinética , Piridonas/uso terapêutico , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacocinética , Rivaroxabana/uso terapêutico , Tiazóis/efeitos adversos , Tiazóis/farmacocinética , Tiazóis/uso terapêutico , Vitamina K/antagonistas & inibidores
20.
Per Med ; 15(3): 209-221, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29767545

RESUMO

Novel oral anticoagulants (NOACs) are becoming a therapy of choice in everyday clinical practice after almost 50 years during which warfarin and related coumarin derivatives were used as the main anticoagulants. Advantages of NOACs over standard anticoagulants include their predictable pharmacodynamics and pharmacokinetics, stable plasma concentrations and less drug-drug and food-drug interactions. However, pharmacogenetics has its place in administration of NOACs, as considerable interindividual variations have been detected. In this review, previous findings in pharmacogenetics of dabigatran, rivaroxaban, apixaban and edoxaban are summarized, along with recommendations for studying genes encoding metabolically important enzymes for four selected NOACs. Future directions include identification of clinically relevant SNPs, and change in optimum dosage for patients who are carriers of significant variants.


Assuntos
Anticoagulantes/farmacocinética , Enzimas/genética , Variantes Farmacogenômicos , Administração Oral , Anticoagulantes/administração & dosagem , Dabigatrana/administração & dosagem , Dabigatrana/farmacocinética , Humanos , Testes Farmacogenômicos , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Piridonas/administração & dosagem , Piridonas/farmacocinética , Rivaroxabana/administração & dosagem , Rivaroxabana/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/farmacocinética
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