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1.
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
2.
Clin Pharmacol Drug Dev ; 8(7): 942-951, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30452784

RESUMO

The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose. Patients were treated for 2 weeks with either placebo (n = 12) or 4 different doses of fulacimstat (5 mg twice daily, n = 9; 10 mg twice daily, n = 9; 25 mg twice daily, n = 10; 50 mg once daily, n = 9). Fulacimstat was safe and well tolerated at all examined doses. There were no clinically relevant effects on vital signs or potassium levels compared with placebo treatment. Mean plasma concentrations of fulacimstat increased with the administered dose and reached exposures predicted to be therapeutically active. The safety profile and the absence of effects on blood pressure or heart rate in a chronic patient population having similar comorbidities and receiving similar comedication as patients after acute MI support future clinical trials with fulacimstat in patients after acute MI.

3.
Clin Pharmacol Drug Dev ; 8(4): 467-479, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-29878583

RESUMO

The orally available chymase inhibitor BAY 1142524 is currently being developed as a first-in-class treatment for left-ventricular dysfunction after myocardial infarction. Results from 3 randomized, single-center, phase 1 studies in healthy male volunteers examining the safety, tolerability, and pharmacokinetics of BAY 1142524 are summarized. In this first-in-human study, single oral doses of 1-200 mg were administered in fasted state as liquid service formulation or immediate release (IR) tablets. The relative bioavailability and the effect of a high-fat/high-calorie meal were investigated at the 5-mg dose. In a multiple-dose escalation study, doses of 5-50 mg twice daily and 100 mg once daily were given for 5 consecutive days. BAY 1142524 was safe and well tolerated and had no effects on heart rate or blood pressure compared with placebo. BAY 1142524 was absorbed with peak concentration 1-3 hours after administration for IR tablets; it was eliminated from plasma with a terminal half-life of 6.84-12.0 hours after administration of liquid service formulation or IR tablets. Plasma exposures appeared to be dose-linear, with a negligible food effect. There was only low accumulation of BAY 1142524 after multiple dosing. BAY 1142524 exhibited a pharmacokinetic profile allowing for once-daily dosing. The absence of blood pressure effects after administration of BAY 1142524 supports the combination of this novel anti-remodeling drug with existing standard of care in patients with left-ventricular dysfunction after acute myocardial infarction.

4.
Thromb J ; 16: 31, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30534007

RESUMO

Background: The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults. Methods: This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5-18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5-2 years, 2-6 years, 6-12 years and 12-18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows. Results: Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study. Conclusions: Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children. Trial registration: ClinicalTrials.gov number, NCT01145859.

5.
Br J Clin Pharmacol ; 84(5): 865-875, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29315699

RESUMO

AIM: Regorafenib is a multikinase inhibitor under investigation for use in neovascular age-related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy volunteers to provide information on safety, tolerability and systemic exposure. METHODS: This was a single-centre, randomized, double-masked, parallel-group, dose-escalation, placebo-controlled study. Subjects received regorafenib eye drops (30 mg ml-1 , 25 µl) as a 0.75 mg single dose (Cohort 1), 0.75 mg twice daily (bid) or thrice daily (tid) over 14 days (Cohorts 2 and 3, respectively), 1.5 mg tid unilaterally for 3 days, then bilaterally for up to 14 days (Cohort 4), or placebo. Plasma samples were taken to estimate systemic exposure. Safety and functional assessments were performed throughout the study. RESULTS: Thirty-six subjects received regorafenib and 12 received placebo. Regorafenib was safe and well tolerated over the dose range. No pathological changes occurred in the anterior, vitreous or posterior eye compartments. Mild eyelid redness, oedema and conjunctival hyperaemia were observed across all regorafenib cohorts; these were comparable with the effects seen with placebo. Predominant symptoms were blurred vision in the active and placebo groups. Systemic safety evaluations showed no clinically relevant findings. Absolute systemic exposure after multiple administrations of regorafenib eye drops at a dose of 0.75 mg was 600-700-fold lower than after multiple oral administration of 160 mg day-1 , the dose approved in cancer indications. CONCLUSION: These results indicate a favourable safety and tolerability profile of regorafenib eye drops up to 30 mg ml-1 tid for use in clinical studies.


Assuntos
Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Administração Oftálmica , Administração Oral , Adolescente , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas/efeitos adversos , Soluções Oftálmicas/farmacocinética , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/sangue , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/administração & dosagem , Piridinas/sangue , Adulto Jovem
6.
Br J Clin Pharmacol ; 78(2): 353-63, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24528331

RESUMO

AIMS: This study investigated relevant pharmacodynamic and pharmacokinetic parameters during the transition from warfarin to rivaroxaban in healthy male subjects. METHODS: Ninety-six healthy men were randomized into the following three groups: warfarin [international normalized ratio (INR) 2.0-3.0] transitioned to rivaroxaban 20 mg once daily (od; group A); warfarin (INR 2.0-3.0) followed by placebo od (group B); and rivaroxaban alone 20 mg od (group C) for 4 days. Anti-factor Xa activity, inhibition of factor Xa activity, prothrombin time (PT), activated partial thromboplastin time, HepTest, prothrombinase-induced clotting time, factor VIIa activity, factor IIa activity, endogenous thrombin potential and pharmacokinetics were measured. RESULTS: An additive effect was observed on the PT and PT/INR during the initial transition period. The mean maximal prolongation of PT was 4.39-fold [coefficient of variation (CV) 18.03%; range 3.39-6.50] of the baseline value in group A, compared with 1.88-fold (CV 10.35%; range 1.53-2.21) in group B and 1.57-fold (CV 9.98%; range 1.37-2.09) in group C. Rivaroxaban had minimal influence on the PT/INR at trough levels. Inhibition of factor Xa activity, activated partial thromboplastin time and endogenous thrombin potential were also enhanced, but to a lesser extent. In contrast, the effects of rivaroxaban on anti-factor Xa activity, HepTest and prothrombinase-induced clotting time were not affected by pretreatment with warfarin. CONCLUSIONS: Changes in pharmacodynamics during the transition from warfarin to rivaroxaban vary depending on the test used. A supra-additive effect on PT/INR is expected during the initial period of transition, but pretreatment with warfarin does not influence the effect of rivaroxaban on anti-factor Xa activity.


Assuntos
Anticoagulantes , Coagulação Sanguínea/efeitos dos fármacos , Morfolinas , Tiofenos , Varfarina , Adolescente , Adulto , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Fator VIIa/análise , Fator Xa/análise , Voluntários Saudáveis , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Morfolinas/farmacocinética , Morfolinas/farmacologia , Protrombina/análise , Tempo de Protrombina , Rivaroxabana , Tiofenos/farmacocinética , Tiofenos/farmacologia , Varfarina/farmacocinética , Varfarina/farmacologia , Adulto Jovem
7.
Clin Pharmacokinet ; 53(1): 1-16, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23999929

RESUMO

Rivaroxaban is an oral, direct Factor Xa inhibitor that targets free and clot-bound Factor Xa and Factor Xa in the prothrombinase complex. It is absorbed rapidly, with maximum plasma concentrations being reached 2-4 h after tablet intake. Oral bioavailability is high (80-100 %) for the 10 mg tablet irrespective of food intake and for the 15 mg and 20 mg tablets when taken with food. Variability in the pharmacokinetic parameters is moderate (coefficient of variation 30-40 %). The pharmacokinetic profile of rivaroxaban is consistent in healthy subjects and across a broad range of different patient populations studied. Elimination of rivaroxaban from plasma occurs with a terminal half-life of 5-9 h in healthy young subjects and 11-13 h in elderly subjects. Rivaroxaban produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for inhibition of Factor Xa activity can be described by an E max model, and prothrombin time prolongation by a linear model. Rivaroxaban does not inhibit cytochrome P450 enzymes or known drug transporter systems and, because rivaroxaban has multiple elimination pathways, it has no clinically relevant interactions with most commonly prescribed medications. Rivaroxaban has been approved for clinical use in several thromboembolic disorders.


Assuntos
Anticoagulantes/farmacocinética , Morfolinas/farmacocinética , Tiofenos/farmacocinética , Anticoagulantes/farmacologia , Interações de Medicamentos , Inibidores do Fator Xa , Humanos , Morfolinas/farmacologia , Rivaroxabana , Tiofenos/farmacologia
8.
Thromb Res ; 132(2): 240-7, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23786894

RESUMO

INTRODUCTION: Rivaroxaban, a direct factor Xa inhibitor, has demonstrated effectiveness for the management of both venous and arterial thrombosis. This study was designed to investigate the antithrombotic effect of rivaroxaban, with or without acetylsalicylic acid (ASA), in an ex vivo perfusion chamber at both low and high shear rates. MATERIALS AND METHODS: Healthy subjects (N=51) were enrolled in a randomized, crossover (rivaroxaban 5, 10 or 20mg with or without ASA), and parallel-group (compared with ASA plus clopidogrel) study. Thrombi formed on pig aorta strips were measured after a 5-minute perfusion at low and high shear rates with blood from the subjects by measuring D-dimer concentration (for fibrin deposition) and P-selectin content (for platelet deposition). RESULTS: ASA alone had no impact on thrombus D-dimer levels, whereas rivaroxaban alone at peak concentrations decreased D-dimer levels by 9%, 84% and 65% at low shear rate and 37%, 73% and 74% at high shear rate after doses of 5, 10 and 20mg, respectively. Steady-state ASA plus rivaroxaban 5mg caused a greater reduction in D-dimer levels (63%) than monotherapy at low shear rate. Co-administration of ASA with clopidogrel was associated with a 30% decrease in D-dimer levels at low shear rate and a 14% decrease at high shear rate. No conclusive effect on P-selectin content was observed across the treatment groups. CONCLUSIONS: Rivaroxaban dose-dependently inhibited ex vivo thrombus formation under low and high shear rates. Co-administration of ASA had an additional effect on the antithrombotic action of low-dose rivaroxaban.


Assuntos
Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Morfolinas/uso terapêutico , Tiofenos/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Adolescente , Adulto , Animais , Anticoagulantes/farmacologia , Aspirina/farmacologia , Estudos Cross-Over , Feminino , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Morfolinas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Rivaroxabana , Suínos , Tiofenos/farmacologia , Trombose/sangue , Trombose/tratamento farmacológico , Tromboembolia Venosa/sangue , Tromboembolia Venosa/patologia , Adulto Jovem
9.
Int J Clin Pharmacol Ther ; 51(7): 549-61, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23458226

RESUMO

OBJECTIVE: Doses of 10 mg, 15 mg, and 20 mg of rivaroxaban are approved for the treatment and prevention of thromboembolic disorders in adult patients. In six Phase I studies, the pharmacokinetics, safety, and tolerability of 2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg rivaroxaban were investigated in healthy male subjects, and the influence of food on these parameters was investigated for the 10 mg, 15 mg, and 20 mg tablet doses. In addition, an oral suspension containing 1 mg/ml rivaroxaban, which is under investigation for future use in the pediatric population, was investigated at doses of 10 mg and 20 mg. MATERIALS: Rivaroxaban was obtained from Bayer Pharma AG, Wuppertal, Germany. METHODS: Six independent, single-dose, cross-over studies were performed in healthy male subjects (between 13 and 24 subjects were enrolled in each study) to determine the pharmacokinetics, safety, and tolerability of rivaroxaban under fasting and fed conditions. Study 1 was an absolute bioavailability study that compared 5 mg and 20 mg tablet doses with a 1 mg intravenous solution. Studies 2 and 3 were confirmatory food-effect studies that assessed 10 mg and 20 mg tablet doses, respectively, under fed and fasting conditions. Study 4 was a formulation study that evaluated oral suspensions of 10 mg (fasting) and 20 mg (fasting and fed) rivaroxaban vs. a 10 mg tablet (fasted). Study 5 was a dose-proportionality study that assessed 2.5 mg, 5 mg, and 10 mg tablets under fasting conditions. Study 6 was a dose-proportionality study that assessed tablet doses of 10 mg, 15 mg, and 20 mg under fed conditions. Pharmacokinetic parameters, including the area under the plasma concentration-time curve after a single dose, the maximum drug concentration in plasma after a single dose, dose-adjusted values of area under the plasma concentration-time curve and maximum drug concentration in plasma after a single dose, half-life associated with the terminal slope, and time to maximum concentration in plasma after a single dose were evaluated. Adverse events were classified according to their degree of severity and were summarized using Medical Dictionary for Regulatory Activities preferred terms. RESULTS: At all doses, rivaroxaban showed an acceptable safety profile and was well tolerated in healthy individuals. Independent of food and formulation, pharmacokinetic parameters of doses up to 10 mg rivaroxaban were dose proportional and had high oral bioavailability (≥ 80%). Under fasting conditions, pharmacokinetic parameters of 15 mg and 20 mg rivaroxaban increased with dose but were less than dose proportional. However, when taken with food, high bioavailability (≥ 80%) of these doses was achieved independent of formulation. CONCLUSION: Pharmacokinetic parameters of doses up to 10 mg rivaroxaban were dose proportional and had high oral bioavailability independent of food or whether administered as tablet or solution. High bioavailability (≥ 80%) of 15 mg and 20 mg rivaroxaban was achieved when taken with food; therefore, these doses need to be taken with food.


Assuntos
Anticoagulantes/farmacocinética , Interações Alimento-Droga , Absorção Intestinal , Morfolinas/farmacocinética , Tiofenos/farmacocinética , Administração Oral , Adulto , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Anticoagulantes/sangue , Anticoagulantes/química , Área Sob a Curva , Disponibilidade Biológica , Química Farmacêutica , Estudos Cross-Over , Relação Dose-Resposta a Droga , Jejum/sangue , Meia-Vida , Humanos , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Modelos Estatísticos , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Morfolinas/sangue , Morfolinas/química , Período Pós-Prandial , Rivaroxabana , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos , Tiofenos/sangue , Tiofenos/química , Adulto Jovem
10.
J Clin Pharmacol ; 53(3): 249-55, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23381840

RESUMO

A randomized, single-blind, placebo-controlled, parallel-group study was conducted to assess the effect of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct Factor Xa inhibitor. Subjects (n = 34) were enrolled into four groups: young males or females (aged 18-45 years) and elderly males or females (aged >75 years), and received a single dose of 10 mg rivaroxaban. Pharmacokinetic and pharmacodynamic parameters were determined. Gender had no significant influence on the pharmacokinetics and pharmacodynamics of rivaroxaban. The area under the concentration-time curve (AUC) of rivaroxaban was 41% higher in elderly compared with young subjects; corresponding AUC values for the inhibition of Factor Xa activity and prolongation of prothrombin time were also higher. These changes were the result of reduced rivaroxaban clearance in elderly subjects, mainly owing to decreased renal function. The influence of age was not considered clinically relevant. The maximum plasma concentration was not increased in elderly subjects, and pharmacodynamic parameters returned close to baseline within 24 hours. The results indicate that age alone and gender did not have a clinically relevant effect on the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy subjects after a 10 mg dose.


Assuntos
Anticoagulantes/farmacologia , Inibidores do Fator Xa , Morfolinas/farmacologia , Tiofenos/farmacologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/sangue , Anticoagulantes/farmacocinética , Feminino , Humanos , Masculino , Morfolinas/sangue , Morfolinas/farmacocinética , Rivaroxabana , Fatores Sexuais , Tiofenos/sangue , Tiofenos/farmacocinética , Adulto Jovem
11.
Br J Clin Pharmacol ; 76(1): 89-98, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23294275

RESUMO

AIM: This study investigated the effects of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban (10 mg), an oral, direct Factor Xa inhibitor. METHOD: This single centre, non-randomized, non-blinded study included subjects with mild (n = 8) or moderate hepatic impairment (n = 8), according to the Child-Pugh classification, and gender-matched healthy subjects (n = 16). RESULTS: Rivaroxaban was well tolerated irrespective of hepatic function. Mild hepatic impairment did not significantly affect the pharmacokinetics or pharmacodynamics of rivaroxaban, compared with healthy subjects. However, in subjects with moderate hepatic impairment, total body clearance was decreased, leading to a significant increase in the area under the plasma concentration-time curve (AUC). The least-squares (LS)-mean values for AUC were 1.15-fold [90% confidence interval (CI) 0.85, 1.57] and 2.27-fold (90% CI 1.68, 3.07) higher in subjects with mild and moderate hepatic impairment, respectively, than in healthy subjects. Consequently, the pharmacodynamic responses were significantly enhanced in subjects with moderate hepatic impairment. For inhibition of Factor Xa, increases in the area under the effect-time curve and the maximum effect were observed, with LS-mean ratios of 2.59 and 1.24, respectively, vs. healthy subjects. Prolongation of prothrombin time was similar in healthy subjects and those with mild hepatic impairment, but was significantly enhanced in those with moderate hepatic impairment. CONCLUSION: Moderate (but not mild) hepatic impairment reduced total body clearance of rivaroxaban after a single 10 mg dose, leading to increased rivaroxaban exposure and pharmacodynamic effects.


Assuntos
Anticoagulantes/farmacocinética , Insuficiência Hepática/fisiopatologia , Morfolinas/farmacocinética , Tiofenos/farmacocinética , Administração Oral , Adulto , Idoso , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacologia , Área Sob a Curva , Estudos de Casos e Controles , Inibidores do Fator Xa , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Morfolinas/farmacologia , Poliaminas , Tempo de Protrombina , Rivaroxabana , Sevelamer , Tiofenos/efeitos adversos , Tiofenos/farmacologia
12.
Br J Clin Pharmacol ; 76(3): 455-66, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23305158

RESUMO

AIMS: The anticoagulant rivaroxaban is an oral, direct Factor Xa inhibitor for the management of thromboembolic disorders. Metabolism and excretion involve cytochrome P450 3A4 (CYP3A4) and 2J2 (CYP2J2), CYP-independent mechanisms, and P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) (ABCG2). METHODS: The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P-gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers. RESULTS: Rivaroxaban did not interact with midazolam (CYP3A4 probe substrate). Exposure to rivaroxaban when co-administered with midazolam was slightly decreased by 11% (95% confidence interval [CI] -28%, 7%) compared with rivaroxaban alone. The following drugs moderately affected rivaroxaban exposure, but not to a clinically relevant extent: erythromycin (moderate CYP3A4/P-gp inhibitor; 34% increase [95% CI 23%, 46%]), clarithromycin (strong CYP3A4/moderate P-gp inhibitor; 54% increase [95% CI 44%, 64%]) and fluconazole (moderate CYP3A4, possible Bcrp [ABCG2] inhibitor; 42% increase [95% CI 29%, 56%]). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4, P-gp/Bcrp (ABCG2) inhibitors (and potential CYP2J2 inhibitors) ketoconazole (158% increase [95% CI 136%, 182%] for a 400 mg once daily dose) and ritonavir (153% increase [95% CI 134%, 174%]). CONCLUSIONS: Results suggest that rivaroxaban may be co-administered with CYP3A4 and/or P-gp substrates/moderate inhibitors, but not with strong combined CYP3A4, P-gp and Bcrp (ABCG2) inhibitors (mainly comprising azole-antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi-pathway inhibitors of rivaroxaban clearance and elimination.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Anticoagulantes/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/farmacocinética , Morfolinas/farmacocinética , Tiofenos/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Adolescente , Adulto , Anticoagulantes/administração & dosagem , Claritromicina/administração & dosagem , Claritromicina/farmacocinética , Claritromicina/farmacologia , Citocromo P-450 CYP3A/administração & dosagem , Inibidores das Enzimas do Citocromo P-450 , Interações de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Eritromicina/administração & dosagem , Eritromicina/farmacocinética , Eritromicina/farmacologia , Humanos , Cetoconazol/administração & dosagem , Cetoconazol/farmacocinética , Cetoconazol/farmacologia , Taxa de Depuração Metabólica , Midazolam/administração & dosagem , Midazolam/farmacocinética , Midazolam/farmacologia , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Rivaroxabana , Especificidade por Substrato , Tiofenos/administração & dosagem , Adulto Jovem
13.
Clin Pharmacol Drug Dev ; 2(3): 270-7, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27121789

RESUMO

Rivaroxaban, an oral, direct factor Xa inhibitor, is currently used in clinical practice for the prevention and treatment of thromboembolic disorders. This single-center, three-way crossover study was designed to investigate the pharmacodynamic effects of rivaroxaban (10 mg) and enoxaparin (40 mg) alone and in combination as well as the influence of enoxaparin on the pharmacokinetics of rivaroxaban in healthy male subjects. When given alone, both drugs exhibited similar, rapid anti-factor Xa activity. Combined administration resulted in an increase of ∼50% in anti-factor Xa activity and a lesser increase in activated partial thromboplastin time, compared with either drug alone. Enoxaparin had no additional effect on prolongation of the prothrombin time induced by rivaroxaban and did not affect the pharmacokinetic parameters of rivaroxaban. The results showed that rivaroxaban (10 mg) and enoxaparin (40 mg) had a similar and rapid onset of action, as indicated by the similar anti-factor Xa activity-time curves, suggesting that both drugs have a similar duration of pharmacological activity at the factor X site. Co-administration of rivaroxaban and enoxaparin is associated with enhanced pharmacodynamic effects.

14.
Pharmaceuticals (Basel) ; 5(3): 279-96, 2012 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-24281379

RESUMO

Dual antiplatelet therapy with acetylsalicylic acid and a thienopyridine, such as clopidogrel, is effective for the secondary prevention of cardiovascular events in patients with acute coronary syndrome, but there is still a substantial residual risk of recurrence. Although anticoagulant therapy with a vitamin K antagonist (e.g. warfarin) in conjunction with antiplatelet therapy has been shown to reduce the risk of cardiovascular events, the rates of bleeding were increased with these combination therapies; hence, triple therapy with warfarin is currently only recommended in patients at low risk of bleeding. In addition, there are other limitations associated with vitamin K antagonist therapy, including the need for routine coagulation monitoring and dose adjustment to maintain the treatment within the therapeutic range. Rivaroxaban is an oral, direct Factor Xa inhibitor; in clinical practice, it is likely that rivaroxaban will be given to patients who also receive antiplatelet therapy, such as clopidogrel. This randomized, non-blinded, three-way crossover study investigated the effect of rivaroxaban on bleeding time when co-administered with clopidogrel. In addition, the influence of clopidogrel on the safety, tolerability, pharmacodynamics and pharmacokinetics of rivaroxaban was investigated. Of 27 healthy male subjects who received a single 300 mg dose of clopidogrel, 14 were identified as clopidogrel responders and were then randomized to the following three treatments: (A) two doses of clopidogrel on two consecutive days (300 mg on day 1; 75 mg on day 2); (B) one dose of rivaroxaban (15 mg); or (C) a combination of treatments A and B (rivaroxaban given on day 2). All treatments were well tolerated. Bleeding time with co-administration of rivaroxaban and clopidogrel was significantly prolonged in four subjects, compared with either drug alone: combination treatment increased the overall least squares-means to 3.77 times baseline (90% confidence interval [CI] 2.82-4.73), compared with 1.13 times baseline (90% CI 0.17-2.09) with rivaroxaban and 1.96 times baseline (90% CI 0.10-2.91) with clopidogrel. Co-administration of clopidogrel had no significant effect on the pharmacokinetics of rivaroxaban and, when compared with rivaroxaban alone, had no further effects on Factor Xa activity or prothrombin time. Inhibition of ADP-stimulated platelet aggregation by clopidogrel was not affected by rivaroxaban. As expected, owing to the mode of action of each study drug, the results of this study demonstrated that co-administration of the Factor Xa inhibitor rivaroxaban and the antiplatelet clopidogrel increased the bleeding time in healthy subjects without affecting other pharmacokinetic or pharmacodynamic parameters of each drug.

15.
Br J Clin Pharmacol ; 70(5): 703-12, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21039764

RESUMO

AIM: This study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10mg single dose), an oral, direct Factor Xa inhibitor. METHODS: Subjects (n= 32) were stratified based on measured creatinine clearance: healthy controls (≥80ml min(-1) ), mild (50-79mlmin(-1) ), moderate (30-49mlmin(-1) ) and severe impairment (<30mlmin(-1) ). RESULTS: Renal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration-time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively. CONCLUSIONS: Rivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.


Assuntos
Inibidores do Fator Xa , Morfolinas/farmacologia , Morfolinas/farmacocinética , Insuficiência Renal/metabolismo , Tiofenos/farmacologia , Tiofenos/farmacocinética , Administração Oral , Adulto , Idoso , Área Sob a Curva , Estudos de Coortes , Creatinina/metabolismo , Feminino , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Rivaroxabana
16.
J Clin Pharmacol ; 50(12): 1429-37, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20350952

RESUMO

To determine acute analgesia by acetylsalicylic acid (ASA) when combined with pseudoephedrine (PSE) in patients with upper respiratory tract infection (URTI), we used the sore throat pain model to measure single-dose effects of ASA 500 mg/PSE 30 mg, ASA 1000 mg/PSE 60 mg, and acetaminophen (APAP) 1000 mg/PSE 60 mg (serving as a positive control). Under double-blind, randomized, placebo-controlled conditions, 640 adult patients with confirmed acute pharyngitis and rhinosinusitis associated with URTI rated throat pain intensity and relief at intervals over 6 hours. Efficacy was demonstrated for both doses of ASA/PSE compared with placebo for all end points, including total pain relief and summed pain intensity differences, beginning at 20 minutes on both scales (all P < .05), and the efficacy of APAP/PSE compared with placebo was confirmed (P < .01). Greater differences in pain relief and intensity were also demonstrated between the higher and lower doses of ASA/PSE (P < .05), in particular, among 329 patients with severe pain, as well as between ASA 1000 mg/PSE 60 mg and APAP 1000 mg/PSE 60 mg (P < .05). No serious adverse events were reported. This study demonstrates that ASA is a well-tolerated and effective analgesic in 500- and 1000-mg doses when combined with pseudoephedrine.


Assuntos
Analgésicos não Entorpecentes/uso terapêutico , Aspirina/uso terapêutico , Descongestionantes Nasais/uso terapêutico , Pseudoefedrina/uso terapêutico , Infecções Respiratórias/tratamento farmacológico , Adolescente , Adulto , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/efeitos adversos , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Resfriado Comum/tratamento farmacológico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Descongestionantes Nasais/administração & dosagem , Descongestionantes Nasais/efeitos adversos , Medição da Dor , Faringite/tratamento farmacológico , Pseudoefedrina/administração & dosagem , Pseudoefedrina/efeitos adversos , Infecções Respiratórias/fisiopatologia , Rinite/tratamento farmacológico , Índice de Gravidade de Doença , Sinusite/tratamento farmacológico , Simpatomiméticos/administração & dosagem , Simpatomiméticos/efeitos adversos , Simpatomiméticos/uso terapêutico , Adulto Jovem
17.
Curr Med Res Opin ; 24(10): 2757-65, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18715524

RESUMO

OBJECTIVE: The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of rivaroxaban--a novel, oral, direct Factor Xa (FXa) inhibitor--in healthy elderly subjects. RESEARCH DESIGN AND METHODS: In this single-centre, single-blind, placebo-controlled, parallel-group, dose-escalation study, 48 subjects (aged 60-76 years) were randomized to receive a single oral dose of 30, 40 or 50 mg of rivaroxaban or placebo. RESULTS: Rivaroxaban was absorbed rapidly, reaching peak plasma concentration (C(max)) 4 h after dosing in all groups. Bioavailability, in terms of the area under the plasma concentration-time curve (AUC) and C(max), increased slightly (less than dose proportionally) after administration of rivaroxaban 40 mg compared with 30 mg, but was not increased further with rivaroxaban 50 mg. Rivaroxaban pharmacodynamic effects (inhibition of FXa activity and prolongation of prothrombin time, activated partial thromboplastin time and HepTest) all showed a similar pattern, with maximum inhibition of FXa activity increasing from 68% after rivaroxaban 30 mg to 75% after 40 mg and no further increase with the 50 mg dose. Most adverse events were mild; observed rates were less than placebo for the 30 and 40 mg dose groups, and similar to placebo for 50 mg. No differences were found between male and female subjects. Effects of rivaroxaban doses above 50 mg were not investigated in this study. CONCLUSIONS: Each single dose of rivaroxaban was well tolerated, with predictable pharmacokinetics and pharmacodynamics at doses up to 40 mg, and provided effective anticoagulation in healthy elderly subjects. Adverse events were somewhat elevated in the 50 mg group, but given the small sample size, no specific conclusions can be drawn about this dosing level.


Assuntos
Inibidores do Fator Xa , Morfolinas/farmacocinética , Tiofenos/farmacocinética , Idoso , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Rivaroxabana , Método Simples-Cego , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos
18.
Drug Saf ; 31(1): 67-77, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18095747

RESUMO

BACKGROUND: Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. Unwanted pro-arrhythmic effects are a common reason for drugs failing to gain regulatory approval; these properties can be detected by assessing the effect of the drug on the QT interval. OBJECTIVE: This study was performed, in accordance with International Conference on Harmonisation (ICH) E14 guidance, to assess whether rivaroxaban prolongs the QT interval. STUDY DESIGN: This was a prospective, randomized, double-blind, double-dummy, four-way crossover study. SETTING: The study was conducted at a clinical pharmacology research unit. SUBJECTS: Healthy male and female subjects (n = 54) aged > or =50 years were enrolled and remained in the study unit for 3 days for each treatment. Of these, 50 patients were eligible for the QT analysis. INTERVENTION: Subjects received single oral doses of rivaroxaban 45 mg or 15 mg, moxifloxacin 400 mg (positive control), or placebo. OUTCOME MEASURES: Multiple ECGs were taken at frequent intervals after drug administration, and the QT interval was measured manually under blinded conditions at a central laboratory. The Fridericia correction formula (QTcF) was used to correct the QT interval for heart rate. The primary outcome was the effect of rivaroxaban or moxifloxacin on the placebo-subtracted QTcF 3 hours after administration. The frequency of outlying QTcF values and the tolerability of the treatments were also assessed. RESULTS: All treatments were well tolerated and had no effect on heart rate. Moxifloxacin established the required assay sensitivity; placebo-subtracted QTcF 3 hours after moxifloxacin administration was prolonged by 9.77 ms (95% CI 7.39, 12.15). Placebo-subtracted QTcF values 3 hours after rivaroxaban administration were -0.91 ms (95% CI -3.33, 1.52) and -1.83 ms (95% CI -4.19, 0.54) with rivaroxaban 45 mg and 15 mg, respectively. QTcF was not prolonged with rivaroxaban at any time, and the frequency of outlying results with rivaroxaban and placebo was similar. CONCLUSION: This thorough QT study, which was performed in accordance with ICH E14 guidelines, shows that rivaroxaban does not prolong the QTc interval. Therefore, the potential of rivaroxaban for the prevention and treatment of thromboembolic disorders, including chronic cardiovascular disorders, can be investigated in appropriate clinical studies without the need for intensive monitoring of the QTc interval.


Assuntos
Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Morfolinas/farmacologia , Tiofenos/farmacologia , Administração Oral , Idoso , Algoritmos , Antitrombina III/administração & dosagem , Antitrombina III/farmacocinética , Antitrombina III/farmacologia , Compostos Aza/sangue , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia/estatística & dados numéricos , Feminino , Fluoroquinolonas , Frequência Cardíaca/fisiologia , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Morfolinas/sangue , Morfolinas/farmacocinética , Moxifloxacina , Estudos Prospectivos , Quinolinas/sangue , Quinolinas/farmacocinética , Quinolinas/farmacologia , Rivaroxabana , Fatores Sexuais , Tiofenos/sangue , Tiofenos/farmacocinética , Fatores de Tempo
19.
J Clin Pharmacol ; 47(11): 1398-407, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17873238

RESUMO

Rivaroxaban (BAY 59-7939) is an oral, direct factor Xa inhibitor in advanced development. This study was undertaken to investigate its effects on thrombin generation. In this placebo-controlled, randomized, crossover study, 12 healthy subjects received rivaroxaban (single 5- or 30-mg dose) or placebo. Thrombin generation was investigated by measuring the endogenous thrombin potential and prothrombinase-induced clotting time. Maximal effect of rivaroxaban was observed 2 hours after drug administration: prothrombinase-induced clotting time was prolonged 1.8 and 2.3 times baseline after rivaroxaban 5 and 30 mg, respectively. Collagen-induced endogenous thrombin potential was reduced by approximately 80% and approximately 90% compared with baseline after rivaroxaban 5 and 30 mg, respectively, and tissue factor-induced endogenous thrombin potential was reduced by approximately 40% (5 mg) and approximately 65% (30 mg), respectively. Thrombin generation remained inhibited for 24 hours. There was a close correlation between plasma concentration of rivaroxaban and prolongation of prothrombinase-induced clotting time and reduction in endogenous thrombin potential. Rivaroxaban strongly inhibits platelet-induced thrombin generation, after activation of either platelets or the coagulation pathway, even in the presence of minimal factor Xa inhibition in plasma.


Assuntos
Anticoagulantes/farmacocinética , Inibidores do Fator Xa , Morfolinas/farmacocinética , Tiofenos/farmacocinética , Administração Oral , Adulto , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/citologia , Plaquetas/enzimologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Fator Xa/análise , Humanos , Masculino , Rivaroxabana , Trombina/análise , Tempo de Trombina , Tromboplastina/análise , Fatores de Tempo
20.
J Clin Pharmacol ; 47(2): 218-26, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17244773

RESUMO

Anticoagulants are often dose adjusted, or their use restricted, in patients with extremes of body weight. Rivaroxaban (BAY 59-7939) is a novel, oral, direct factor Xa inhibitor in clinical development. This was a randomized, single-blind, placebo-controlled, parallel-group study in healthy male and female subjects to assess the effect of extreme body weight (< or = 50 kg and >120 kg), and gender, on the safety, tolerability, pharmacokinetics, and pharmacodynamics of rivaroxaban 10 mg, compared with subjects of normal weight (70-80 kg). Rivaroxaban was well tolerated. Cmax of rivaroxaban was unaffected in subjects >120 kg but was increased by 24% in subjects weighing < or = 50 kg, resulting in a small (15%) increase in prolongation of prothrombin time, which was not considered clinically relevant. The area under the curve was unaffected by body weight or gender. No other clinically relevant differences were observed, suggesting that rivaroxaban is unlikely to require dose adjustment for body weight or gender.


Assuntos
Anticoagulantes/farmacologia , Anticoagulantes/farmacocinética , Peso Corporal , Morfolinas/farmacologia , Morfolinas/farmacocinética , Tiofenos/farmacologia , Tiofenos/farmacocinética , Adulto , Anticoagulantes/efeitos adversos , Antitrombina III/efeitos adversos , Antitrombina III/farmacocinética , Antitrombina III/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Rivaroxabana , Tiofenos/efeitos adversos
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