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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
2.
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
3.
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
4.
Anal Chim Acta ; 1076: 18-31, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31203961

RESUMO

Direct oral anticoagulants (DOACs) are first-line drugs used for the treatment of venous thromboembolism and prevention of stroke in patients with atrial fibrillation. These drugs do not require the regular biochemical monitoring that is mandatory for warfarin, and they exhibit shorter half-lives and have a faster onset of action. Since recent real-world studies evidence a higher prevalence of adverse side effects than what was anticipated in clinical trials, monitoring the plasma concentrations of DOACs is being used to personalize their pharmacotherapy, in accordance to the characteristics of the patient, and to evaluate the adherence to therapy. In order to fulfill the aforementioned clinical unmet needs, there are specific coagulation assays that indirectly assess the plasma concentrations of DOACs. Nevertheless, these assays are not sufficiently accurate or sensitive. For this reason, liquid chromatography techniques coupled to mass spectrometry detection, are considered the gold standard method to accurately determine plasma concentrations of DOACs. Therefore, the present paper provides the first comprehensive review of the current analytical methods that were developed and validated for the quantitative determination of apixaban, dabigatran, rivaroxaban and/or edoxaban and their main metabolites in biological samples. The chromatographic methods will be particularly highlighted and an emphasis will be placed on the major difficulties faced during optimization and development steps. In addition, the physicochemical, pharmacokinetic and pharmacodynamic characteristics of each drug will be critically related to chromatographic conditions. Their influence on the pre-treatment procedures and storage conditions of DOACs will be examined, suggesting strategies that should be applied to accurately quantify DOACs in biological samples.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Inibidores do Fator Xa/análise , Animais , Estabilidade de Medicamentos , Inibidores do Fator Xa/sangue , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/urina , Humanos
5.
Heart Vessels ; 34(12): 2011-2020, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31123819

RESUMO

The aims of this study were to determine the distribution of plasma concentration of edoxaban (PC-Ed) with their 90% interval (on therapy range) and its correlation with anticoagulation markers in patients with non-valvular atrial fibrillation (NVAF). Consecutive 97 NVAF patients under edoxaban therapy were evaluated (60/30 mg dose, n = 48/49; men/women, n = 71/26; age, 69 years). CHADS2 score 0, 1, and ≥ 2 were 27%, 44%, and 29%, respectively. The mean (90% interval) of PC-Ed by LC-MS/MS was 194.3 (49.4-345.3) and 17.0 (4.8-40.7) ng/mL at peak (2-4 h post-dose) and trough (pre-dose), respectively. Correlation of prothrombin time (PT) with PC-Ed was higher than that of activated partial thromboplastin time (aPTT). Among 6 PT reagents, Coagupia PT-N and Simplastin Excel S (both PT reagents) showed the highest predictive capability for the upper outlier of PC-Ed at peak and trough. Among 4 aPTT reagents, only Thrombocheck APTT measured at peak had a significant predictive capability. When using PT reagents, both peak and trough sampling showed a similar predictive capability for the upper outliers of PC-Ed with a high sensitivity, but a relatively low specificity. We demonstrated the distributions of plasma concentration, PT with 6 reagents, and aPTT with 4 reagents under edoxaban therapy in Japanese patients with NVAF, showing their 90% intervals. For predicting the upper outlier of PC-Ed, PT was more sensitive compared with aPTT, whereas predicting capability for the outliers of PC-Ed was mostly similar between peak and trough samplings among PT reagents (UMIN 000032492).


Assuntos
Fibrilação Atrial/sangue , Tempo de Tromboplastina Parcial/métodos , Tempo de Protrombina/métodos , Piridinas/farmacocinética , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/farmacocinética , Administração Oral , Idoso , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Feminino , Seguimentos , Humanos , Incidência , Japão/epidemiologia , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Piridinas/administração & dosagem , Curva ROC , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Tiazóis/administração & dosagem , Resultado do Tratamento
6.
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
7.
Semin Liver Dis ; 39(2): 195-208, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30978730

RESUMO

Direct-acting oral anticoagulants (DOACs) have provided benefit in patients requiring anticoagulation for certain diseases by decreasing the burden of subcutaneous injections and the requirement for frequent monitoring through regular blood tests, to ensure adequacy of the therapeutic doses. Studies have demonstrated DOACs to be as safe, and in some instance safer, compared with traditional anticoagulants in the general population. However, the studies evaluating DOACs excluded patients with cirrhosis, a condition associated with an increased risk of developing portal vein thrombosis (PVT). Warfarin or low-molecular weight heparin are the standard-of-care treatment for acute PVT in cirrhosis, although there is enthusiasm in a paradigm shift switching to DOACs for the treatment of acute PVT in cirrhosis, particularly since the release of DOAC antidotes. This article reviews the current Food and Drug Administration-approved DOACs, hepatic metabolism of DOACs, pharmacokinetics of DOACs in patients with cirrhosis, safety of DOACs (including bleeding, hepatotoxicity, and pregnancy), current treatment guidelines for PVT in cirrhosis, and studies evaluating the use of DOACs in cirrhosis and for the treatment of PVT in cirrhosis. The potential use of DOACs for PVT primary prophylaxis in at-risk patients with cirrhosis and the possible antifibrotic effects of DOACs are also discussed.


Assuntos
Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Cirrose Hepática/complicações , Fígado/efeitos dos fármacos , Veia Porta/efeitos dos fármacos , Trombose Venosa/tratamento farmacológico , Administração Oral , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Inibidores do Fator Xa/efeitos adversos , Feminino , Humanos , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Trombose Venosa/complicações
8.
Expert Rev Cardiovasc Ther ; 17(4): 319-330, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30897988

RESUMO

INTRODUCTION: Edoxaban is the last direct oral anticoagulant marketed for the prevention of stroke among patients with nonvalvular atrial fibrillation (AF). Areas covered: ENGAGE AF-TIMI 48 was the pivotal clinical trial that led to the approval of edoxaban 60 mg once daily. After the publication of this study, a great number of substudies and post hoc analyses have been published, together with some observational studies. The aim of this review was to update the current evidence about the use of edoxaban in AF patients. Expert opinion: In the ENGAGE AF-TIMI 48 trial, edoxaban 60 mg was noninferior to warfarin for the prevention of stroke or systemic embolism, but significantly reduced the risk of bleeding, major adverse cardiac events and death from cardiovascular causes. The relative efficacy and safety of edoxaban 60 mg compared with warfarin were independent of different clinical conditions, such as prior stroke, age, risk of falls, renal function, hepatic disease, ischemic heart disease, heart failure, valvular heart disease, or cancer. Data about the effectiveness and safety of edoxaban in real-life patients are scarce, but consistent with those of the pivotal clinical trial. Edoxaban seems a cost-effective alternative to warfarin among AF patients with moderate to high thromboembolic risk.


Assuntos
Fibrilação Atrial/complicações , Inibidores do Fator Xa/uso terapêutico , Piridinas/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/uso terapêutico , Tromboembolia/prevenção & controle , Anticoagulantes/uso terapêutico , Ensaios Clínicos como Assunto , Análise Custo-Benefício , Inibidores do Fator Xa/farmacocinética , Hemorragia/induzido quimicamente , Humanos , Piridinas/farmacocinética , Acidente Vascular Cerebral/etiologia , Tiazóis/farmacocinética , Tromboembolia/etiologia , Varfarina/uso terapêutico
9.
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
10.
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
12.
Int J Lab Hematol ; 41(3): 309-315, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30698331

RESUMO

INTRODUCTION: Co-administration of enoxaparin and a direct oral factor Xa inhibitor (xabans: apixaban, edoxaban, rivaroxaban) could give rise to the problem of overlapping the anti-Xa activity when measuring direct oral anticoagulant (DOAC) levels. We aimed to evaluate in vitro the degree of the interference of increasing enoxaparin concentrations on xaban plasma levels measured by different chromogenic anti-Xa assays with drug-specific calibrators and controls. METHODS: Seven plasma samples were spiked with apixaban, edoxaban, or rivaroxaban at fixed concentration, and enoxaparin at increasing concentrations (0, 0.125, 0.250, 0.50, 1.0, 1.50, and 2.0 IU/mL). The evaluated chromogenic assays were as follows: Biophen DiXaI and Biophen Heparin LRT (Hyphen BioMed), Berichrom Heparin and Innovance Heparin (Siemens), STA-Liquid Anti-Xa (Stago Diagnostics), Technochrom anti-Xa (Technoclone), and HemosIL Liquid Anti-Xa (Werfen). RESULTS: The presence of enoxaparin caused increased DOAC levels, with over-estimation depending on the anti-Xa assay and on the heparin concentration in the sample. The smallest over-estimation was in the sample with enoxaparin 0.125 IU/mL and the greatest in the sample with enoxaparin 2.0 IU/mL (0%, 3.1%, and 7.4% vs 583.8%, 526.1%, and 415.2% for apixaban, edoxaban, and rivaroxaban, respectively). Biophen DiXaI showed lower interference compared to other methods (maximum over-estimation in the presence of enoxaparin 2.0 IU/mL: 56.4% dosing rivaroxaban by Biophen DIXaI vs 583.8% dosing apixaban by Berichrom Heparin). CONCLUSION: The presence of enoxaparin interferes with xabans measurement by chromogenic anti-Xa assays causing falsely elevated DOAC levels, the over-estimation being dependent on the anti-Xa assay and on the heparin concentration in the sample.


Assuntos
Testes de Coagulação Sanguínea/métodos , Enoxaparina/farmacocinética , Inibidores do Fator Xa/farmacocinética , Técnicas In Vitro , Enoxaparina/administração & dosagem , Inibidores do Fator Xa/administração & dosagem , Humanos
13.
Int J Lab Hematol ; 41(2): 250-261, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30604921

RESUMO

INTRODUCTION: Chromogenic anti-Xa assays are the most appropriate tests to estimate the amount of betrixaban in plasma but the sensitivity of available tests is limited and improvements are needed to encompass the on-therapy range. METHODS: Betrixaban was spiked at concentrations ranging from 0 to 500 ng/mL in plasma from healthy donors. Three commercial tests were used (Biophen® DiXaI® , STA® Liquid Anti-Xa, and HemosIL® Liquid Anti-Xa), and adaptation of their sample dilution scheme was performed. These new methodologies were also tested on plasma spiked with amounts of unfractionated heparin (UFH), low molecular weight heparins (LMWH), or fondaparinux covering the on-therapy ranges to evaluate their sensitivity to indirect factor Xa inhibitors. RESULTS: Results showed concentration-dependent decreases in OD/min inversely proportional to the dilutions. While modifications improve the sensitivity of these tests to betrixaban (eg, ½*OD/min of 502 ng/mL [95% CI: 495-508 ng/mL] for Biophen® DiXaI® [1:50] is reduced to 51 ng/mL [95% CI: 50-52 ng/mL] for improved Biophen® DiXaI® [1:5]), results also showed an increased sensitivity to indirect factor Xa inhibitors, except for Biophen® DiXaI® which remains insensitive to UFH and LMWH. CONCLUSIONS: Results showed that the improvement of current chromogenic anti-Xa methodologies enhances the sensitivity of these assays to betrixaban but also to indirect factor Xa inhibitors. This lack of specificity may lead to overestimation of betrixaban concentrations in patients bridged with heparins. To avoid this cross-interference, the use of the Biophen® DiXaI® may be a solution except for fondaparinux which remains active even in the presence of the Biophen® DiXaI® 's specific buffer. For the other chromogenic assays, the conception and validation of specific buffer is required.


Assuntos
Benzamidas/farmacocinética , Análise Química do Sangue/métodos , Inibidores do Fator Xa/farmacocinética , Piridinas/farmacocinética , Feminino , Humanos , Masculino
15.
Eur J Drug Metab Pharmacokinet ; 44(1): 111-120, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30132264

RESUMO

BACKGROUND: Amblyomin-X is a recombinant protein under development for cancer treatment owing to its selective cytotoxic activity over several tumour cell lines and tumour regression in mice models. The aim of this study was to examine the distribution and pharmacokinetics of amblyomin-X in healthy female mice. METHODS: Amblyomin-X was injected intravenously into the healthy animals and at controlled times plasma and organs were removed and analysed for identification and quantification of the protein. Alternatively, the labelled protein was injected into mice and tracked in an in vivo imaging system. RESULTS: Amblyomin-X was rapidly eliminated from plasma, probably because of its inability to bind to plasma albumin. After 10 min, the protein was found in the thymus and lungs, and later in the heart, liver and kidneys. In the liver, the protein was found until 24 h after a single injection. The in vivo analysis showed the same kinetics profile, besides the identification of amblyomin-X in the bladder region, indicating its elimination via urine. Only fragments of amblyomin-X were observed in the urine. CONCLUSIONS: These findings suggest that amblyomin-X is rapidly distributed to the tissues, metabolized by the liver or even kidneys, and eliminated in urine in healthy mice. There is no accumulation in any organ.


Assuntos
Antineoplásicos/farmacocinética , Inibidores do Fator Xa/farmacocinética , Proteínas e Peptídeos Salivares/farmacocinética , Administração Intravenosa , Sequência de Aminoácidos , Animais , Antineoplásicos/administração & dosagem , Inibidores do Fator Xa/administração & dosagem , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas e Peptídeos Salivares/administração & dosagem , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia
16.
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
18.
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
19.
Int J Lab Hematol ; 41(2): 200-207, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30407740

RESUMO

INTRODUCTION: Direct oral anticoagulants (DOAC) are commonly prescribed and measuring drug levels may be useful in a number of contexts. However, data on DOAC level measurement and their clinical utility in real-world studies are limited. METHODS: We carried out a 2-year retrospective cohort study of DOAC levels measured at our institution. RESULTS: One hundred and sixty-nine levels measured in 113 patients were included in the final analysis. Our patients had a median age of 69.9. AF was the commonest indication for anticoagulation. Median turnaround time for inpatient levels was 92 minutes. Median FXa inhibitor levels within 6 hours of last dose and following one half-life were similar to those described previously. However, the range of levels was wider than expected. Importantly, some levels remained in an on therapy range even after 3 half-lives. There was no correlation between dabigatran level and time from last dose. The reason for request varied with setting; 23 outpatient levels were to monitor drug efficacy, whereas 54 and 43 inpatient levels were collected in the context of bleeding and emergency surgery respectively. 60.3% of levels had an impact on clinical decision making. CONCLUSION: Our real-world study demonstrates that DOAC levels can be performed in a timely manner to influence clinical decision making. In addition, it suggests there is a wide variation in levels such that it can be difficult to predict in the real world. Overall, this supports the wider use of DOAC levels to help guide clinicians in managing patients taking these drugs.


Assuntos
Monitoramento de Medicamentos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Centros de Atenção Terciária , Reino Unido
20.
Br J Clin Pharmacol ; 85(1): 270-272, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30421528

RESUMO

A 67-year-old man was admitted to the emergency department about 5 h after deliberate self-poisoning with 300 mg of Apixaban. The clinical examination did not show any organ dysfunctions or haemorrhagic signs, and the patient's life was not in danger. The first analysis, upon admission, showed a concentration of 2655 µg l-1 of Apixaban. The Cmax was observed 17 h after the intake (3654 µg l-1 ), about four times the classical Tmax value (median [range]: 4 h [2-4]). The Apixaban was then eliminated following a first order elimination with a calculated half-life of 10.8 h. The anti-Xa activity seems to be linearly related to concentration up to 4000 µg l-1 . This report suggests that the use of activated charcoal should be effective up to 17 h after a massive intake.


Assuntos
Depressão/complicações , Overdose de Drogas/sangue , Inibidores do Fator Xa/farmacocinética , Pirazóis/farmacocinética , Piridonas/farmacocinética , Idoso , Depressão/psicologia , Overdose de Drogas/etiologia , Overdose de Drogas/psicologia , Inibidores do Fator Xa/envenenamento , Meia-Vida , Humanos , Masculino , Pirazóis/envenenamento , Piridonas/envenenamento , Comprimidos
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