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1.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1130-1131: 121808, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669631

RESUMO

A new sample extraction protocol was developed for pharmacokinetic studies of dabigatran with high-performance liquid chromatography separation - electrospray ionization time-of-flight mass spectrometry analysis. After protein precipitation with acetonitrile, free dabigatran and its metabolites are separated into water phase by water-dichloromethane liquid-liquid extraction to purify the sample from proteins and endogenous lipophilic compounds. Chromatographic separation was achieved on an Agilent Zorbax SB-CN column (150 × 4.6 mm, 5 µm)) using 0.1% aqueous solution of formic acid and acetonitrile (80:20) as the mobile phase. Agilent Zorbax SB-CN column was selected to improve sample resolution and to avoided early elution of dabigatran previously seen when using a C18 column. The extended calibration curve was constructed from 5 to 1000 ng/L while precision and accuracy were assessed at four levels across the linear dynamic ranges. Within-run precision was <5.6% and the between-run precision was <3.9%. The method accuracy ranged from 89.8% to 104.4%. The developed method was successfully applied to 30 patient samples to evaluate antithrombotic efficacy and anticoagulant activity of dabigatran following knee endoprosthesis surgery.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Dabigatrana/sangue , Dabigatrana/isolamento & purificação , Espectrometria de Massas em Tandem/métodos , Dabigatrana/farmacocinética , Monitoramento de Medicamentos , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes
2.
Clin Appl Thromb Hemost ; 25: 1076029619867137, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31364394

RESUMO

To describe the effect of dabigatran on thrombin time (TT) reagents at different concentrations of thrombin. Pooled normal plasma enriched with dabigatran was dissolved in dimethylsulfoxide (DMSO) at concentrations of 0, 20, 50, 100, 200, 300, and 500 ng/mL. Samples with each concentration were evaluated using a semiautomatic coagulation analyzer to assess the effect of dabigatran on internal normalized ratio (INR), thromboplastin time (APTT), and TT, which were purchased from Instrument Laboratory (IL), Sysmex (SYS), and Stago (STA), respectively. Regarding INR, no reagent showed good sensitivity to increasing concentration of dabigatran, despite all reagents showing good linear response curves (P = .012). Regarding APTT, all reagents had low sensitivity to increasing dabigatran concentration, but SYS-APTT showed a better linear response curve (P = .001). Regarding TT, all reagents had a good linear response to the concentration of dabigatran; however, SYS-TT was very sensitive at low concentrations of dabigatran (0-100 ng/mL), while IL (TT-5 mL) and STA-TT were sensitive at medium concentrations of dabigatran (0-300 ng/mL), and IL (TT-2 mL) was less sensitive for a wide concentration of dabigatran (0-500 ng/mL; P = .007). Internal normalized ratio and APTT showed low sensitivity and SYS-TT showed high sensitivity to concentrations of dabigatran that were unsuitable to monitor. Both IL (TT-5 mL) and STA-TT were useful at medium concentrations of dabigatran by semiautomatic coagulation analyzer, which calculated results using the end point method of coagulation. Instrument Laboratory (TT-2 mL), which contains a higher concentration of thrombin, had better sensitivity to the concentration of dabigatran than APTT and was suitable for routine monitoring by an automatic analyzer.


Assuntos
Dabigatrana/farmacocinética , Monitoramento de Medicamentos/métodos , Tempo de Trombina , Antitrombinas/sangue , Antitrombinas/farmacocinética , Testes de Coagulação Sanguínea , Dabigatrana/sangue , Dabigatrana/normas , Monitoramento de Medicamentos/instrumentação , Monitoramento de Medicamentos/normas , Humanos , Indicadores e Reagentes/farmacologia , Tempo de Tromboplastina Parcial , Sensibilidade e Especificidade , Trombina/farmacologia
3.
Int J Clin Pharm ; 41(3): 682-686, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31016680

RESUMO

Background The direct oral anticoagulants (DOACs) offer several advantages over warfarin in the management atrial fibrillation, including the provision of fixed dosing without a requirement for regular monitoring. Recently however the subject of DOAC monitoring has been probed after several post-hoc analyses demonstrated an association between plasma levels and efficacy and safety events. Objective The aim of this pilot study was to explore the acceptability of DOAC plasma monitoring amongst patients with atrial fibrillation and the factors that may influence these attitudes. Method A simple DOAC monitoring schedule based on the dabigatran pharmacokinetic profile was developed. A cross-sectional survey was distributed to patients with atrial fibrillation asking them to indicate their likelihood of taking a particular DOAC subjected to plasma monitoring. Results Thirty patients participated in the study. Most patients (63.3%) favoured taking a DOAC subjected to monitoring under the proposed schedule, citing increased efficacy and reduced toxicity as the reasons for their response. Conclusion There is some suggestion that atrial fibrillation patients may in fact favour taking a DOAC subjected to infrequent monitoring if this enhanced safety and efficacy.


Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/sangue , Fibrilação Atrial/sangue , Fibrilação Atrial/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/psicologia , Estudos Transversais , Dabigatrana/administração & dosagem , Dabigatrana/sangue , Monitoramento de Medicamentos/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto
4.
J Thromb Thrombolysis ; 47(3): 403-408, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30600427

RESUMO

There are no clear and consistent guidelines on how to utilize DOAC assays, and reports on the use of DOAC levels in clinical practice is limited. The objective of this study was to analyze why DOAC levels are ordered, how the results affect clinical decision-making, and to determine if DOAC assays are utilized appropriately. This was a retrospective chart review study analyzing 150 dabigatran, rivaroxaban, and apixaban levels performed at a single institution. The majority of DOAC assays were ordered in situations or special patient populations where confirming absence or detecting presence of drug may be useful. The most common indication for ordering assays was prior to an invasive procedure. Most DOAC levels were timed appropriately but peak levels were most likely to be incorrectly ordered. Clinical decisions following level results depended on indication for ordering and were most commonly used to determine whether or not to proceed with an invasive procedure. The results of our study suggest while DOAC assays are generally ordered for useful indications, there is still a lack of understanding of when levels should be drawn and how to interpret DOAC assay results.


Assuntos
Monitoramento de Medicamentos/métodos , Inibidores do Fator Xa/sangue , Padrões de Prática Médica/normas , Anticoagulantes/sangue , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Dabigatrana/sangue , Dabigatrana/farmacologia , Dabigatrana/uso terapêutico , Tomada de Decisões , Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico , Feminino , Humanos , Masculino , Pirazóis/sangue , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridonas/sangue , Piridonas/farmacologia , Piridonas/uso terapêutico , Estudos Retrospectivos , Rivaroxabana/sangue , Rivaroxabana/farmacologia , Rivaroxabana/uso terapêutico , Procedimentos Cirúrgicos Operatórios/métodos
5.
PLoS One ; 14(1): e0209350, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30615630

RESUMO

BACKGROUND: Idarucizumab is a humanized Fab fragment that specifically reverses dabigatran anticoagulation. In trauma, volume expanders are used for resuscitation to compensate for blood loss and hemorrhagic shock, but it is unknown whether volume expanders influence the binding of dabigatran to its antidote. Using a porcine dilutional coagulopathy model, this study investigated whether volume replacement strategies affect binding of dabigatran to idarucizumab. METHODS: Twenty-five male pigs were treated orally with dabigatran etexilate (30 mg/kg bid) for 3 days. The following day, animals were anesthetized, infused with dabigatran (total dose 0.645 mg/kg) to achieve supratherapeutic concentrations, and randomized 1:1:1:1:1 (n = 5 per group) to control (no hemodilution) or hemodilution where ~50% of blood volume was substituted with Ringer's solution, 6% hydroxyethyl starch 130/0.4, 6% hydroxyethyl starch 200/0.5 or 4% gelatin. Idarucizumab was then administered intravenously (30 mg/kg) and serial blood samples were taken for up to 24 hours to measure diluted thrombin time (corresponding with dabigatran activity), total dabigatran (bound to antidote and free drug) and a panel of coagulation parameters. RESULTS: Mean plasma dabigatran levels were 617 ± 16 ng/mL after infusion and 600 ± 114 ng/mL after ~50% hemodilution with no significant differences between groups. Following treatment with idarucizumab, plasma concentrations of unbound dabigatran decreased markedly, with similar reductions in all groups. Dabigatran-induced prolongation of coagulation parameters was rapidly reversed in all groups. CONCLUSION: This study indicates that several volume expanders used for resuscitation in trauma do not interfere with the binding of idarucizumab to dabigatran.


Assuntos
Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/farmacocinética , Antídotos/farmacocinética , Antitrombinas/sangue , Antitrombinas/farmacocinética , Dabigatrana/antagonistas & inibidores , Dabigatrana/farmacocinética , Hemodiluição , Animais , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/terapia , Volume Sanguíneo/fisiologia , Dabigatrana/sangue , Masculino , Modelos Animais , Substitutos do Plasma/administração & dosagem , Substitutos do Plasma/metabolismo , Sus scrofa
6.
Eur Heart J Cardiovasc Pharmacother ; 5(2): 91-99, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30608563

RESUMO

AIMS: Effective anticoagulation in patients undergoing electrical cardioversion (ECV) for symptomatic atrial fibrillation is important to prevent adverse events. High medication adherence is a requirement. In patients with newly diagnosed atrial fibrillation (n = 169) who were intended to undergo ECV, the aim of this study was to measure self-reported short- and long-term adherence, evaluate whether dabigatran plasma concentrations reflect adherence, measure treatment satisfaction and assess whether adherence and treatment satisfaction are correlated. METHODS AND RESULTS: Plasma concentrations (liquid-chromatography tandem mass spectrometry), the 8-point Morisky Medication Adherence Scale (MMAS-8) and the Anti-Clot Treatment Scale (ACTS) were measured after 3 weeks and 7 weeks of treatment. Combined mean peak (1-3 h after intake) and trough (10-16 h after intake) plasma concentrations were 175 (SD 109) ng/mL and 75 (SD 45) ng/mL, respectively. There was no relationship between short-term adherence (last 3 days) or long-term adherence (last 3-4 weeks) and plasma concentrations, unless the last intake was more than 48 h ago. After 7 weeks high, moderate, and low adherence, according to the MMAS-8, was seen in 74%, 21%, and 5% of patients, respectively. Treatment satisfaction was high (median ACTS score 68.5, range 46-75 points). Treatment satisfaction and adherence were not correlated. CONCLUSION: The percentage of patients in the high adherence group (74%) was lower than expected, which is a matter of concern. Dabigatran plasma concentrations could not detect short- or long-term non-adherence, unless the drug was last taken more than 48 h ago. Treatment satisfaction did not correlate with adherence.


Assuntos
Antitrombinas/administração & dosagem , Fibrilação Atrial/terapia , Dabigatrana/administração & dosagem , Cardioversão Elétrica , Adesão à Medicação , Idoso , Antitrombinas/sangue , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Cromatografia Líquida , Dabigatrana/sangue , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Satisfação do Paciente , Estudos Prospectivos , Autorrelato , Espectrometria de Massas em Tandem , Fatores de Tempo , Resultado do Tratamento
7.
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
8.
J Formos Med Assoc ; 118(7): 1154-1160, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30581104

RESUMO

BACKGROUND/PURPOSE: Dabigatran is effective in preventing ischemic stroke and systemic embolism in patients with atrial fibrillation. Although the therapeutic window for dabigatran is wide, its pharmacokinetic properties can differ between specific populations. This study aimed to establish a real-life plasma dabigatran concentration database and investigate potential factors affecting this concentration in Asians. METHODS: Patients under dabigatran therapy were recruited. Plasma dabigatran concentration was determined in trough and peak blood samples by using ultra-high performance liquid chromatography with tandem mass spectrometry analysis. Factors affecting the dabigatran concentration were investigated. RESULTS: A total of 46 patients (33 male, 71.7%) were prospectively enrolled. Most of them were receiving a low dose regimen (110 mg twice daily, n = 38, 82.6%). The trough and peak concentrations were significantly correlated (p < 0.001), and the trough concentration was higher in patients aged ≥75 years, body weight ≤60 kg, creatinine clearance (CrCl) ≤50 mL/min, CHA2DS2-VASc score >3 points, and HAS-BLED score ≥3 points. Multiple linear regression analysis identified body weight and serum creatinine as key factors predicting trough concentration (p = 0.003 and 0.005, respectively). Importantly, drug adherence was the only independent factor associated with low trough concentration, defined as the lowest 20th percentile in our study cohort (n = 10, hazard ratio = 9.07; 95% CI, 1.12 to 73.22; p = 0.004). CONCLUSION: Dabigatran monitoring may be considered for patients at risk of overexposure, especially those with low body weight and renal insufficiency, and also for detecting those with extremely low drug concentration.


Assuntos
Antitrombinas/sangue , Fibrilação Atrial/sangue , Dabigatrana/sangue , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Creatinina/sangue , Dabigatrana/administração & dosagem , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Modelos Lineares , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/prevenção & controle , Taiwan
10.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1100-1101: 43-49, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30292948

RESUMO

Direct Oral Anticoagulants (DOACs) available for the treatment and prevention of thromboembolic diseases include dabigatran, a direct thrombin (IIa) inhibitor, and apixaban, edoxaban and rivaroxaban, which are direct inhibitors of Stuart factor (Xa). DOACs have a different pharmacokinetic and pharmacodynamics profiles, with less probable drug-drug interactions than vitamin K antagonists. They do not require systematic therapeutic monitoring except in specific clinical situations such as emergency procedures or drug non-compliance. Furthermore, anticoagulant effects of DOACs could be impacted by renal impairment, drug-drug interactions, food interactions, or pharmacogenetic variability. In this context, we developed a method for simultaneous determination of dabigatran, rivaroxaban and apixaban in human plasma using high performance liquid chromatography coupled with a mass spectrometry assay and applied it to 26 patient samples. Our method presents a total run time of 5 min and extends from 25 to 1000 µg/L for apixaban and dabigatran; and from 5 to 1000 µg/L for rivaroxaban. Intra- and inter-assay accuracy were between -22.3 and 25.4%; and - 23.7 and 3.8%, respectively. Precision at low and high concentrations were below 17.5%. Frozen samples were stable up to 3 months. No significant cross-contamination was observed. In conclusion, our assay can be used during clinical studies and in daily routine practice for the management of specific clinical situations at reasonable cost.


Assuntos
Anticoagulantes/sangue , Cromatografia Líquida de Alta Pressão/métodos , Dabigatrana/sangue , Pirazóis/sangue , Piridonas/sangue , Rivaroxabana/sangue , Espectrometria de Massas em Tandem/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Lineares , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
11.
J Thromb Haemost ; 16(12): 2462-2470, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30288934

RESUMO

Essentials A rapid test to detect thrombin inhibition by dabigatran would be valuable in acute situations. A thrombin-based trigger was applied in whole blood using rotation thromboelastometry. Effects of dabigatran were assessed in vitro and in samples from patients on dabigatran. The test produced data rapidly and was sensitive to dabigatran concentrations from 20 to 500 ng mL-1 . SUMMARY: Background Rapid determination of the anticoagulant effect of dabigatran is essential in emergency situations. Objective To study a viscoelastic test (rotational thromboelastometry [ROTEM]) for rapid determination of dabigatran effects in whole blood samples. Method ROTEM measurements were performed with comparison of two triggers (thrombin-based versus the commercial tissue factor-based trigger Ex-tem) in samples from 10 healthy donors spiked with dabigatran (20-500 ng mL-1 ) and in samples from 35 patients receiving dabigatran treatment; 10 healthy subjects served as controls. Clotting time (CT) and the difference in CT without versus with addition of the dabigatran antidote idarucizumab (CTdiff ) were measured. Addition of idarucizumab reveals the contribution of dabigatran to ROTEM measurements and its potential reversibility. Results In vitro studies showed that thrombin CT and thrombin CTdiff were more sensitive than Ex-tem CT and Ex-tem CTdiff in detecting dabigatran in whole blood samples. In patient samples, when thrombin CT and thrombin CTdiff were used, it was possible to detect dabigatran with a cut-off of dabigatran at 20 ng mL-1 , whereas, when Ex-tem CT and Ex-tem CTdiff were used, the method was less sensitive. Data from patient samples were obtained within 15 min of blood sampling. Conclusions ROTEM CT with a thrombin-based trigger is more sensitive to dabigatran effects than Ex-tem CT, and detects anticoagulant effects of drug concentrations in the low-very low therapeutic range. Analysis with idarucizumab (CTdiff ) reveals dabigatran-specific effects. As data are rapidly obtained, this method could, with further development and validation of its performance, be suitable for detecting clinically significant dabigatran effects in emergency situations.


Assuntos
Antitrombinas/sangue , Fibrilação Atrial/tratamento farmacológico , Coagulação Sanguínea/efeitos dos fármacos , Dabigatrana/sangue , Monitoramento de Medicamentos/métodos , Testes Imediatos , Tromboelastografia , Trombina/metabolismo , Adulto , Idoso , Antitrombinas/uso terapêutico , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Estudos de Casos e Controles , Dabigatrana/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudo de Prova de Conceito , Fluxo de Trabalho
12.
Clin Lab ; 64(10): 1611-1621, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30336535

RESUMO

BACKGROUND: Detection of new oral anticoagulant (NOAC) levels by screening, special and global tests, and liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS) is important in clinical situations when the cause of bleeding needs to be determined. METHODS: We compared a routine coagulation test, special function test for NOACs, global coagulation test, and an LC-MS/MS method that enables simultaneous determination of apixaban, dabigatran and rivaroxaban in human plasma within one analysis to determine the optimal indication of the comparison methods, including their limitations and interferences. RESULTS: This study was conducted on a set of blood samples from 116 patients treated with NOACs. The results of both specific dilute thrombin time (dTT) tests for dabigatran provided the same results as the activated partial thromboplastin time (aPTT) screening test in comparison with LC-MS/MS as a reference. The dTT assay HemosIL® showed better results for low concentrations when compared to LC-MS/MS than dTT HYPHEN® as HemosIL® uses a non-linear calibration curve. Results of the specific anti-Xa assay yielded better results than the prothrombin time test in comparison with LC-MS/MS as a reference, especially for apixaban, but also for rivaroxaban. Our LC MS/MS method is simply feasible, but only in a specialized laboratory. The method is easy-to-use for the simultaneous determination of all dabigatran, apixaban and rivaroxaban by LC-MS/MS within three minutes with a concentration range of 1 to 500 µg/L without dilution. CONCLUSIONS: In the normal practice of the coagulation laboratory, it is advisable to use specific tests for NOAC determination as screening and global assays are not sufficiently specific. The dTT test is the optimal choice for dabigatran determination and for xabans to determine anti-Xa activity. The LC-MS/MS method is suitable as an arbitration method for serious conditions.


Assuntos
Anticoagulantes/sangue , Testes de Coagulação Sanguínea/métodos , Cromatografia Líquida/métodos , Inibidores do Fator Xa/sangue , Espectrometria de Massas em Tandem/métodos , Administração Oral , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Dabigatrana/administração & dosagem , Dabigatrana/sangue , Dabigatrana/uso terapêutico , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/uso terapêutico , Humanos , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Embolia Pulmonar/prevenção & controle , Pirazóis/administração & dosagem , Pirazóis/sangue , Pirazóis/uso terapêutico , Piridonas/administração & dosagem , Piridonas/sangue , Piridonas/uso terapêutico , Rivaroxabana/administração & dosagem , Rivaroxabana/sangue , Rivaroxabana/uso terapêutico , Trombina/metabolismo , Trombose Venosa/prevenção & controle
13.
Thromb Res ; 171: 160-166, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30316961

RESUMO

INTRODUCTION: Calibrated automated thrombinography (CAT) is a sensitive method to assess coagulation. Dabigatran inhibits both free thrombin and the α2macroglobulin (α2M)-thrombin complex, which results in an erroneously increased peak and endogenous thrombin potential (ETP) without affecting lag time and time-to-peak. The aim of this study was to elucidate the artefacts in CAT when dabigatran is present. MATERIALS AND METHODS: Thrombin generation (TG) was measured in vitro by using CAT in the presence or absence of 6 µM idarucizumab in plasma spiked with dabigatran. Additionally, ex vivo measurements were performed in plasmas of 63 patients using dabigatran in the presence and absence of idarucizumab. RESULTS: The in vitro experiments confirmed that the ETP, peak and velocity index were artificially increased. This was mainly due to the inhibition of the calibrator by dabigatran and partly due to CAT algorithms. The calibration artefact could be resolved by adding idarucizumab to the calibrator well. However, the second, mathematical artefact remains when dabigatran is present in the TG well. These findings were corroborated by ex vivo experiments i.e. the lag time and time-to-peak were significantly reduced in patients upon addition of idarucizumab, but the ETP and peak were not significantly affected. The velocity index did change significantly, since this is a combination of time-dependent factors and the peak. CONCLUSIONS: The peak, ETP and velocity index do not represent the anticoagulant effect of dabigatran on TG measured with CAT. The lag time and time-to-peak, however, do reflect the effect of dabigatran.


Assuntos
Antitrombinas/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Dabigatrana/farmacologia , Trombina/metabolismo , Antitrombinas/sangue , Testes de Coagulação Sanguínea/métodos , Calibragem , Dabigatrana/sangue , Humanos , Trombina/análise
15.
Thromb Res ; 171: 62-67, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30261356

RESUMO

BACKGROUND: In patients who are receiving dabigatran, a direct oral anticoagulant, measuring the anticoagulant effect before surgery may be needed in certain circumstances. Although the dilute thrombin time (dTT) can reliably measure dabigatran levels, it is not consistently available. More commonly used coagulation tests, including the activated partial thromboplastin time (aPTT) and thrombin time (TT) might have clinical utility but their accuracy is uncertain. METHODS: 103 patients stopped dabigatran 1-4 days before an elective surgery/procedure as part of a standardized dabigatran interruption protocol. With a blood sample taken just before surgery, we assessed the accuracy of five aPTT assays (Actin FS, Stago PTT, C.K. PREST, HemosIL aPTT-SP, SynthASil) and TT to measure the residual anticoagulant effect of dabigatran. We determined the sensitivity, specificity and other accuracy indices of these assays to predict a dabigatran level > 30 ng/mL as determined by a reference standard test, the dTT (Hemoclot). RESULTS: Of five aPTT reagents, four assays had excellent (100%) and one assay had good (93%) sensitivity to detect a level of dabigatran > 30 ng/mL, but all had insufficient specificity (50-74%). A TT > 90 s had good sensitivity (93%) and excellent specificity (100%). CONCLUSION: Five aPTT assays had good sensitivity but poor specificity to detect low levels of dabigatran (≤30 ng/mL) after standardized dabigatran interruption before an elective surgery/procedure, thereby limiting the use of aPTT as an alternative to the dTT in preoperative settings.


Assuntos
Antitrombinas/sangue , Antitrombinas/farmacologia , Dabigatrana/sangue , Dabigatrana/farmacologia , Tempo de Tromboplastina Parcial/métodos , Tempo de Trombina/métodos , Antitrombinas/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Dabigatrana/uso terapêutico , Monitoramento de Medicamentos/métodos , Procedimentos Cirúrgicos Eletivos , Humanos , Indicadores e Reagentes , Estudos Prospectivos
18.
Drugs Aging ; 35(6): 539-544, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29736814

RESUMO

BACKGROUND: The number of elderly individuals with non-valvular atrial fibrillation (NV-AF) requiring long-term anticoagulation is rising. The pharmacokinetics of oral anticoagulants in elderly individuals may differ from that for younger patients. The aim of this study was to assess the dabigatran levels in elderly patients with NV-AF. PATIENTS AND METHODS: A pilot prospective post-marketing study in patients with NV-AF on dabigatran therapy was performed; we enrolled 21 consecutive elderly patients (aged ≥ 75 years) on a reduced dabigatran regimen (110 mg twice daily) and compared them with 13 younger (≤ 70 years) individuals on reduced dabigatran therapy due to renal impairment and with 16 younger patients on standard dabigatran therapy (150 mg twice daily). Blood samples were taken for the assessment of dabigatran trough and peak levels. Dabigatran levels were measured with the Hemoclot® Thrombin Inhibitor Assay. RESULTS: There were significant differences in dabigatran trough levels when comparing elderly patients on reduced dabigatran with non-elderly patients on reduced dabigatran (99.3 ± 73.6 vs 51.6 ± 25.6 ng/mL; p < 0.01). Similarly, the detected dabigatran peak levels were significantly higher in elderly patients on reduced dabigatran compared with non-elderly patients on reduced dabigatran (173.4 ± 116.2 vs 116.1 ± 19.1 ng/mL; p < 0.01). No significant differences in dabigatran trough and peak levels were found when comparing elderly patients on reduced dabigatran with non-elderly patients on standard dabigatran therapy. CONCLUSION: This pilot study demonstrated that elderly patients on reduced dabigatran exhibit significantly higher dabigatran levels than younger individuals on a reduced regimen, and similar levels compared with younger individuals on standard dabigatran.


Assuntos
Anticoagulantes/sangue , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/sangue , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Dabigatrana/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos
19.
J Cardiovasc Pharmacol Ther ; 23(5): 399-406, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29695165

RESUMO

INTRODUCTION: Dabigatran etexilate is an oral direct thrombin inhibitor. Dabigatran excretion is 80% renal, so exposure increases with severity of renal failure. The US Food and Drug Administration-approved dabigatran etexilate 75 mg twice daily (BID) for patients with nonvalvular atrial fibrillation (NVAF) having severely impaired renal function (creatinine clearance: 15-30 mL/min), based on post hoc pharmacokinetic modeling. We assessed dabigatran exposure at trough and peak levels in patients with NVAF and severely impaired renal function and compared with model predictions. METHODS: Patients received dabigatran etexilate (75 mg BID) for ≥7 days before blood sampling; Cpre,ss (steady-state predose concentration; trough) was taken 10 to 16 hours postdose (prior to next dose), and C2,ss (steady-state concentration; peak) was taken 2 hours (± 30 minutes) postdose. Pharmacodynamic parameters at baseline (Ebase), trough concentrations (Epre,ss), and peak concentrations (E2,ss) were assessed by established coagulation assays. RESULTS: Of the 150 patients screened, 60 were treated, of which 40% were male and 78.3% were white; median age was 84 years. Cpre,ss values (n = 51) were close to pharmacokinetic modeling predictions with a geometric mean (gMean) of 155 ng/mL, geometric coefficient of variation (gCV) of 76.9%, and range of 15.6 to 498 ng/mL. The C2,ss values (n = 59) had a gMean of 202 ng/mL, gCV of 70.6%, and range of 42.0 to 680 ng/mL. Pharmacodynamic effects on coagulation paralleled dabigatran concentrations. Eleven (18.3%) patients had ≥1 adverse event (AE); pharmacokinetic results for these patients versus those without AEs (n = 49) were Cpre, ss: gMean = 206 versus 145 ng/mL, gCV = 64.0% versus 78.3%; C2,ss: gMean = 243 versus 193 ng/mL, gCV = 68.9% versus 70.8%. All bleeding events (8 events in 5 patients) were considered minor by the investigators. CONCLUSION: Dabigatran exposure levels largely confirmed earlier pharmacokinetic predictions, supporting the use of dabigatran etexilate 75 mg BID in patients with NVAF and severely impaired renal function. Pharmacodynamic results were also in agreement with earlier studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01896297.


Assuntos
Antitrombinas/administração & dosagem , Antitrombinas/farmacocinética , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/administração & dosagem , Dabigatrana/farmacocinética , Nefropatias/fisiopatologia , Rim/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/efeitos adversos , Antitrombinas/sangue , Fibrilação Atrial/sangue , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Biomarcadores/sangue , Creatinina/sangue , Dabigatrana/efeitos adversos , Dabigatrana/sangue , Esquema de Medicação , Feminino , Hemorragia/induzido quimicamente , Humanos , Nefropatias/sangue , Nefropatias/complicações , Nefropatias/diagnóstico , Masculino , Modelos Biológicos , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
20.
Ther Drug Monit ; 40(3): 369-376, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29578938

RESUMO

BACKGROUND: Direct oral anticoagulants (DOACs) are prescribed for anticoagulation in patients with atrial fibrillation and venous thromboembolic disease. Fixed doses are recommended, but measuring their serum drug concentrations as a basis for dose adjustments may be useful in some clinical settings. METHODS: An ultra-high-performance liquid chromatography-tandem mass spectrometry method for the analysis of the DOACs apixaban, dabigatran, edoxaban, and rivaroxaban in human serum was developed and validated. A 100-µL serum sample was handled using a pipetting robot. Protein precipitation was performed with 375 µL of 1% formic acid in acetonitrile (vol/vol), and phospholipid removal was performed using a Waters Ostro 96-well plate. The injection volume was 1 µL, and run time was 3.0 minutes. RESULTS: The calibration range was 5-800 nmol/L. The between-day precision relative SDs were in the range of 3.3%-10%. Recoveries ranged from 85% to 105%, and matrix effects from 88% to 102%, when corrected with internal standard. Edoxaban was, in contrast to the other DOACs, unstable when stored for more than 6 hours at 30°C. The suitability of the method was demonstrated by analyzing routine samples from 345 patients undergoing anticoagulation treatment. CONCLUSIONS: The developed method fulfilled the set validation criteria, and its suitability was demonstrated in a routine setting. The instability of edoxaban may complicate the transport of routine samples to the laboratory.


Assuntos
Dabigatrana/sangue , Pirazóis/sangue , Piridinas/sangue , Piridonas/sangue , Rivaroxabana/sangue , Espectrometria de Massas em Tandem/normas , Tiazóis/sangue , Antitrombinas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Cromatografia Líquida/métodos , Cromatografia Líquida/normas , Inibidores do Fator Xa/sangue , Humanos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
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