RESUMO
PURPOSE: To characterize the safety, pharmacodynamics, and pharmacokinetics (PK) of vericiguat in healthy males. METHODS: Six phase I studies were conducted in European, Chinese, and Japanese males. Subjects received oral vericiguat as a single dose (0.5-15.0 mg solution [for first-in-human study] or 1.25-10.0 mg immediate release [IR tablets]) or multiple doses (1.25-10.0 mg IR tablets once daily [QD] or 5.0 mg IR tablets twice daily for 7 consecutive days). Bioavailability and food effects on vericiguat PK (IR tablets) were also studied in European subjects. RESULTS: Overall, 255 of 265 randomized subjects completed their respective studies. There were no deaths or serious adverse events. Vericiguat was generally well tolerated at doses ≤ 10.0 mg. In the first-in-human study, the most frequent drug-related adverse events were headache and postural dizziness (experienced by five subjects each [7.2%]). Three of four subjects who received vericiguat 15.0 mg (oral solution, fasted) experienced orthostatic reactions. Vericiguat (≤ 10.0 mg, IR tablets) was rapidly absorbed (median time to reach maximum plasma concentration ≤ 2.5 h [fasted]) with a mean half-life of about 22.0 h (range 17.9-27.0 h for single and multiple doses). No evidence for deviation from dose proportionality or unexpected accumulation was observed. Administration of vericiguat 5.0 mg IR tablets with food increased bioavailability by 19% (estimated ratio 119% [90% confidence interval]: 108; 131]), reduced PK variability, and prolonged vericiguat absorption relative to the fasted state. CONCLUSION: In general, vericiguat was well tolerated. These results supported further clinical evaluation of vericiguat QD in patients with heart failure. REGISTRY NUMBERS: EudraCT: 2011-001627-21; EudraCT: 2012-000953-30.
Assuntos
Compostos Heterocíclicos com 2 Anéis , Pirimidinas , Guanilil Ciclase Solúvel , Administração Oral , Adulto , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , GMP Cíclico/sangue , GMP Cíclico/urina , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/farmacocinética , Método Duplo-Cego , Esquema de Medicação , Epinefrina/sangue , Interações Alimento-Droga , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/administração & dosagem , Compostos Heterocíclicos com 2 Anéis/efeitos adversos , Compostos Heterocíclicos com 2 Anéis/sangue , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Humanos , Masculino , Norepinefrina/sangue , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/sangue , Pirimidinas/farmacocinética , Método Simples-Cego , Resistência Vascular/efeitos dos fármacosRESUMO
Anticoagulant plasma concentrations and patient characteristics might affect the benefit-risk balance of therapy. The study objective was to assess the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism (VTE) prophylaxis (VTE-P) after hip/knee replacement surgery. Post hoc exposure-response analyses were conducted using data from the phase 3 RECORD1-4 studies, in which 12,729 patients were randomized to rivaroxaban 10 mg once daily or enoxaparin for ≤ 39 days. Multivariate regression approaches were used to correlate model-predicted individual rivaroxaban exposures and patient characteristics with outcomes. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and by making use of the known correlation between rivaroxaban plasma concentration and dynamics of PT. No significant associations between rivaroxaban exposure and total VTE or major bleeding were identified. A significant association between exposure and a composite of major or non-major clinically relevant (NMCR) bleeding from day 4 after surgery was observed. The relationship was shallow, with an approximate predicted absolute increase in a composite of major or NMCR bleeding from 1.08 [95% confidence interval (CI) 0.76-1.54] to 2.18% (95% CI 1.51-3.17) at the 5th and 95th percentiles of trough plasma concentration, respectively. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit-risk could be identified within the investigated exposure range. Hence, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-P.
Assuntos
Artroplastia de Quadril/efeitos adversos , Monitoramento de Medicamentos , Hemorragia , Complicações Pós-Operatórias , Risco Ajustado/métodos , Rivaroxabana , Tromboembolia Venosa , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Anticoagulantes/sangue , Biomarcadores Farmacológicos/análise , Quimioprevenção/métodos , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/estatística & dados numéricos , Feminino , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/prevenção & controle , Prognóstico , Tempo de Protrombina/métodos , Medição de Risco , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Rivaroxabana/sangue , Tromboembolia Venosa/sangue , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controleRESUMO
Anticoagulant plasma concentrations and patient characteristics might affect the benefit-risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN-DVT and EINSTEIN-PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure-response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure-efficacy relationships were shallow. Exposure-safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit-risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T.
Assuntos
Monitoramento de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Risco Ajustado/métodos , Rivaroxabana , Tromboembolia Venosa , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Anticoagulantes/sangue , Biomarcadores Farmacológicos/análise , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Prognóstico , Tempo de Protrombina/métodos , Medição de Risco , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Rivaroxabana/sangue , Índice Terapêutico , Resultado do Tratamento , Tromboembolia Venosa/sangue , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/tratamento farmacológicoRESUMO
Recently, the European Medicines Agency (EMA) published the new draft guideline on the pharmacokinetic and clinical evaluation of modified release (MR) formulations. The draft guideline contains the new requirement of performing multiple dose (MD) bioequivalence studies, in the case when the MR formulation is expected to show 'relevant' drug accumulation at steady state (SS). This new requirement reveals three fundamental issues, which are discussed in the current work: first, measurement for the extent of drug accumulation (MEDA) predicted from single dose (SD) study data; second, its relationship with the percentage residual area under the plasma concentration-time curve (AUC) outside the dosing interval (τ) after SD administration, %AUC(τ-∞)SD ; and third, the rationale for a threshold of %AUC(τ-∞)SD that predicts 'relevant' drug accumulation at SS. This work revealed that the accumulation ratio RA,AUC , derived from the ratio of the time-averaged plasma concentrations during τ at SS and after SD administration, respectively, is the 'preferred' MEDA for MR formulations. A causal relationship was derived between %AUC(τ-∞)SD and RA,AUC , which is valid for any drug (product) that shows (dose- and time-) linear pharmacokinetics regardless of the shape of the plasma concentration-time curve. Considering AUC thresholds from other guidelines together with the causal relationship between %AUC(τ-∞)SD and RA,AUC indicates that values of %AUC(τ-∞)SD ≤ 20%, resulting in RA,AUC ≤ 1.25, can be considered as leading to non-relevant drug accumulation. Hence, the authors suggest that 20% for %AUC(τ-∞)SD is a reasonable threshold and selection criterion between SD or MD study designs for bioequivalence studies of new MR formulations.
Assuntos
Área Sob a Curva , Preparações de Ação Retardada/farmacocinética , Guias de Prática Clínica como Assunto/normas , Disponibilidade Biológica , Humanos , Modelos Biológicos , Equivalência TerapêuticaRESUMO
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 CYP2J2 , Citocromo P-450 CYP3A/administração & dosagem , Inibidores das Enzimas do Citocromo P-450 , Interações Medicamentosas , 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 JovemRESUMO
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/farmacologiaRESUMO
Unlike traditional anticoagulants, the more recently developed agents rivaroxaban, dabigatran and apixaban target specific factors in the coagulation cascade to attenuate thrombosis. Rivaroxaban and apixaban directly inhibit Factor Xa, whereas dabigatran directly inhibits thrombin. All three drugs exhibit predictable pharmacokinetic and pharmacodynamic characteristics that allow for fixed oral doses in a variety of settings. The population pharmacokinetics of rivaroxaban, and also dabigatran, have been evaluated in a series of models using patient data from phase II and III clinical studies. These models point towards a consistent pharmacokinetic and pharmacodynamic profile, even when extreme demographic factors are taken into account, meaning that doses rarely need to be adjusted. The exception is in certain patients with renal impairment, for whom pharmacokinetic modelling provided the rationale for reduced doses as part of some regimens. Although not routinely required, the ability to measure plasma concentrations of these agents could be advantageous in emergency situations, such as overdose. Specific pharmacokinetic and pharmacodynamic characteristics must be taken into account when selecting an appropriate assay for monitoring. The anti-Factor Xa chromogenic assays now available are likely to provide the most appropriate means of determining plasma concentrations of rivaroxaban and apixaban, and specific assays for dabigatran are in development.
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 JovemRESUMO
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: ⢠Population pharmacokinetics and pharmacodynamics of rivaroxaban have been characterized in healthy subjects and in patients with total venous thromboembolism, deep vein thrombosis or atrial fibrillation. WHAT THIS STUDY ADDS: ⢠This article is the first description of the population pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in patients with acute coronary syndrome (ACS). It is the largest population pharmacokinetic and pharmacodynamic study on rivaroxaban conducted to date (n= 2290). The PK and PK-PD relationship of rivaroxaban in patients with ACS were similar to those in other patient populations. In addition, model-based simulations showed that the influence of renal function and age on the exposure to rivaroxaban in the ACS population were similar to the findings from Phase 1 special population studies. These findings suggest that rivaroxaban has highly predictable PK-PD and may provide a consistent anticoagulant effect across the studied patient populations, which allows an accurate prediction of the dose to control anticoagulation optimally. AIMS: The aim of this analysis was to use a population approach to facilitate the understanding of the pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndrome (ACS) and to evaluate the influence of patient covariates on the exposure of rivaroxaban in patients with ACS. METHODS A population pharmacokinetic model was developed using pharmacokinetic samples from 2290 patients in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46. The relationship between pharmacokinetics and the primary pharmacodynamic end point, prothrombin time, was evaluated. RESULTS: The pharmacokinetics of rivaroxaban in patients with ACS was adequately described by an oral one-compartment model. The estimated absorption rate, apparent clearance and volume of distribution were 1.24 h(-1) (interindividual variability, 139%), 6.48 l h(-1) (31%) and 57.9 l (10%), respectively. Simulations indicate that the influences of renal function, age and bodyweight on exposure in ACS patients are consistent with the findings in previous Phase 1 studies. Rivaroxaban plasma concentrations exhibit a close-to-linear relationship with prothrombin time in the ACS population, with little interindividual variability. The estimated pharmacokinetic and pharmacodynamic parameters for the ACS patients were comparable to those for venous thromboembolism prevention, deep vein thrombosis and atrial fibrillation patients. CONCLUSIONS: The similarity in pharmacokinetics/pharmacodynamics of rivaroxaban among different patient populations and the low interindividual variability in the exposure-prothrombin time relationship indicate that the anticoagulant effect of rivaroxaban is highly predictable and consistent across all the patient populations studied.
Assuntos
Síndrome Coronariana Aguda/metabolismo , Anticoagulantes/farmacocinética , Morfolinas/farmacocinética , Tiofenos/farmacocinética , Síndrome Coronariana Aguda/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/farmacologia , Ensaios Clínicos Fase I como Assunto , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Morfolinas/farmacologia , Protrombina/metabolismo , Rivaroxabana , Tiofenos/farmacologia , Adulto JovemRESUMO
Rivaroxaban is a direct inhibitor of factor Xa, a coagulation factor at a critical juncture in the blood coagulation pathway leading to thrombin generation and clot formation. It is selective for human factor Xa, for which it has >10 000-fold greater selectivity than for other biologically relevant serine proteases (half-maximal inhibitory concentration [IC(50)], >20 micromol/L). Rivaroxaban inhibits factor Xa in a concentration-dependent manner (inhibitory constant [K(i)], 0.4 nmol/L) and binds rapidly (kinetic association rate constant [k(on)], 1.7x10(7) mol/L(-1) s(-1)) and reversibly (kinetic dissociation rate constant [k(off)], 5x10(-3) s(-1)). By inhibiting prothrombinase complex-bound (IC(50), 2.1 nmol/L) and clot-associated factor Xa (IC(50), 75 nmol/L), rivaroxaban reduces the thrombin burst during the propagation phase. In animal models of venous and arterial thrombosis, rivaroxaban showed dose-dependent antithrombotic activity. In healthy individuals, rivaroxaban was found to have predictable pharmacokinetics and pharmacodynamics across a 5- to 80-mg total daily dose range, inhibiting factor Xa activity and prolonging plasma clotting time. In phase III clinical trials, rivaroxaban regimens reduced rates of venous thromboembolism in patients after total hip or knee arthroplasty compared with enoxaparin regimens, without significant differences in rates of major bleeding, showing that rivaroxaban has a favorable benefit-to-risk profile.
Assuntos
Inibidores do Fator Xa , Morfolinas/uso terapêutico , Tiofenos/uso terapêutico , Trombose Venosa/tratamento farmacológico , Administração Oral , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibrinolíticos/administração & dosagem , Fibrinolíticos/farmacocinética , Fibrinolíticos/uso terapêutico , Humanos , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Rivaroxabana , Tiofenos/administração & dosagem , Tiofenos/farmacocinética , Trombose Venosa/prevenção & controleRESUMO
BACKGROUND: Cinaciguat (BAY 58-2667) is the first of a new class of soluble guanylate cyclase activators in clinical development for acute decompensated heart failure. We aimed to assess the hemodynamic effects, safety, and tolerability of intravenous cinaciguat in patients with acute decompensated heart failure (pulmonary capillary wedge pressure > or =18 mm Hg). METHODS AND RESULTS: After initial dose finding (part A; n=27), cinaciguat was evaluated in the nonrandomized, uncontrolled proof-of-concept part of the study (part B; n=33) using a starting dose of 100 microg/h, which could be titrated depending on hemodynamic response. Patients were categorized as responders if their pulmonary capillary wedge pressure decreased by > or =4 mm Hg compared with baseline. Final doses of cinaciguat after 6 hours of infusion in part B were 50 microg/h (n=2), 200 microg/h (n=12), and 400 microg/h (n=16). Compared with baseline, a 6-hour infusion of cinaciguat led to significant reductions in pulmonary capillary wedge pressure (-7.9 mm Hg), mean right atrial pressure (-2.9 mm Hg), mean pulmonary artery pressure (-6.5 mm Hg), pulmonary vascular resistance (-43.4 dynes . s . cm(-5)), and systemic vascular resistance (-597 dynes . s . cm(-5)), while increasing heart rate by 4.4 bpm and cardiac output by 1.68 L/min. The responder rate was 53% after 2 hours, 83% after 4 hours, and 90% after 6 hours. Cinaciguat was well tolerated, with 13 of 60 patients reporting 14 drug-related treatment-emergent adverse events of mild to moderate intensity, most commonly hypotension. CONCLUSIONS: Cinaciguat has potent preload- and afterload-reducing effects, increasing cardiac output. Further investigation of cinaciguat for acute decompensated heart failure is warranted.
Assuntos
Benzoatos/uso terapêutico , Guanilato Ciclase/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Vasodilatadores/uso terapêutico , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Benzoatos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Feminino , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipotensão/induzido quimicamente , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Pressão Propulsora Pulmonar/efeitos dos fármacos , Guanilil Ciclase Solúvel , Resistência Vascular/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversos , Vasodilatadores/farmacologiaRESUMO
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 , RivaroxabanaRESUMO
BACKGROUND: Vericiguat is a stimulator of soluble guanylate cyclase currently under investigation as a first-in-class therapy for worsening chronic heart failure (NCT02861534). Patients with heart failure often require polypharmacy because of comorbidities. Hence, understanding the clearance mechanisms, elimination, and potential for pharmacokinetic drug-drug interactions of vericiguat is important for dose recommendations in this patient population. METHODS: Biotransformation and perpetrator properties of vericiguat were characterized in vitro using human hepatocytes, liver microsomes, and recombinant enzymes. This was complemented by a human mass balance study and ten drug-drug interaction studies in healthy volunteers wherein vericiguat was co-administered orally with omeprazole, magnesium/aluminum hydroxide, ketoconazole, rifampicin, mefenamic acid, midazolam, warfarin, digoxin, sacubitril/valsartan, aspirin, or sildenafil. RESULTS: In the human mass balance study, mean total radioactivity recovered was 98.3% of the dose administered (53.1% and 45.2% excreted via urine and feces, respectively). The main metabolic pathway of vericiguat is glucuronidation via uridine diphosphate-glucuronosyltransferase 1A9 and 1A1. In vitro studies revealed a low risk of vericiguat acting as a perpetrator by inhibiting cytochrome P450s, uridine diphosphate-glucuronosyltransferase isoforms, or major transport proteins, or by inducing cytochrome P450s. These observations were supported by phase I drug-drug interaction studies. Phase I studies that assessed the propensity of vericiguat as a victim drug showed changes in the range that did not warrant recommendations for dose adjustment in phase III. CONCLUSIONS: A low pharmacokinetic interaction potential of vericiguat was estimated from in vitro data and confirmed in vivo. Thus, vericiguat is suitable for a patient population with multiple comorbidities requiring polypharmacy.
Assuntos
Ativadores de Enzimas/farmacocinética , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Pirimidinas/farmacocinética , Adolescente , Adulto , Idoso , Ensaios Clínicos Fase I como Assunto , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Guanilil Ciclase Solúvel , Adulto JovemRESUMO
AIMS: To investigate the safety, pharmacokinetics and pharmacodynamics of rivaroxaban, an oral, direct Factor Xa (FXa) inhibitor, in healthy, male Chinese subjects. METHODS: Two randomized, single-blind, placebo-controlled, dose-escalation studies were conducted in healthy Chinese men aged 18-45 years. In the single-dose study, subjects received single, oral doses of rivaroxaban 2.5, 5, 10, 20 and 40 mg. In the multiple-dose study, oral rivaroxaban was administered in doses of 5, 10, 20 and 30 mg twice daily for 6 days. RESULTS: Rivaroxaban, in single and multiple doses up to 60 mg, was well tolerated. Rapid absorption was observed in both studies (time to C(max) 1.25-2.5 h). In the multiple-dose study, rivaroxaban exposure increased dose-proportionally after the first dose and at steady state (for the 5-20-mg doses). The half-life of rivaroxaban was up to 7.9 h in the single-dose study. Maximal inhibition of FXa activity was achieved within 1-3 h of dosing in the single-dose study [at 20 mg FXa inhibition as a median percentage change from baseline, 45.92; 95% confidence interval (CI) 44.64, 50.70] and 2-3 h after administration at steady state in the multiple-dose study (at 20 mg median FXa inhibition as a median percentage change from baseline, 60.25; 95% CI 56.16, 63.05), in line with maximum rivaroxaban plasma concentrations. CONCLUSIONS: Rivaroxaban demonstrated predictable pharmacokinetics and pharmacodynamics in healthy Chinese subjects, in line with findings observed previously in White subjects. This suggests that fixed doses of rivaroxaban may be administered to all patients, regardless of their ethnic origin.
Assuntos
Antitrombina III/administração & dosagem , Inibidores do Fator Xa , Morfolinas/administração & dosagem , Tiofenos/administração & dosagem , Adolescente , Adulto , Antitrombina III/farmacocinética , Antitrombina III/farmacologia , Povo Asiático/etnologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/farmacocinética , Morfolinas/farmacologia , Rivaroxabana , Método Simples-Cego , Tiofenos/farmacocinética , Tiofenos/farmacologia , Adulto JovemRESUMO
Riociguat, a first-in-class soluble guanylate cyclase stimulator, is approved for the treatment of pulmonary arterial hypertension (PAH), a serious potential complication of human immunodeficiency virus (HIV) infection. This open-label study investigated the pharmacokinetic drug-drug interaction potential of antiretroviral therapies on riociguat exposure in HIV-infected adults. HIV-infected adults without PAH on stable antiretroviral regimens (efavirenz/emtricitabine/tenofovir disoproxil, emtricitabine/rilpivirine/tenofovir disoproxil, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil, abacavir/dolutegravir/lamivudine, or a ritonavir-boosted triple regimen) for ≥ 6 weeks received a single riociguat dose (0.5 mg). Riociguat pharmacokinetics and safety were assessed; pharmacokinetics was compared with historical healthy volunteer data. Of 41 participants treated (n = 8 in each arm, except n = 9 in the ritonavir-boosted triple regimen arm), 40 were included in the pharmacokinetic analyses. Riociguat median tmax was 1.00-1.27 h, with comparable maximum concentration (Cmax) across the five background antiretroviral groups. Riociguat exposure was highest with abacavir/dolutegravir/lamivudine, followed by elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil > emtricitabine/rilpivirine/tenofovir disoproxil > ritonavir-boosted triple regimen > efavirenz/emtricitabine/tenofovir disoproxil; riociguat area under the plasma concentration versus time curve (AUC) was approximately threefold higher with abacavir/dolutegravir/lamivudine than efavirenz/emtricitabine/tenofovir disoproxil. Compared with historical data, riociguat exposure in HIV-infected adults was similar when co-administered with efavirenz/emtricitabine/tenofovir disoproxil, slightly increased when administered with ritonavir-boosted triple regimen and increased by approximately threefold when administered with abacavir/dolutegravir/lamivudine. Riociguat was well tolerated, with no new safety findings. Riociguat was well tolerated in adults with HIV on stable background antiretroviral therapy although an apparent increase in AUC of riociguat was observed in patients receiving abacavir/dolutegravir/lamivudine. Patients should be monitored closely during riociguat initiation and dose adjustment for signs and symptoms of hypotension.
RESUMO
Prothrombin time (PT) is a measure of coagulation status and was assessed in the majority of patients in the rivaroxaban phase II and III clinical trials as a pharmacodynamic marker. In the absence of sufficient phase III pharmacokinetic (PK) data to provide individual exposure measures for input into rivaroxaban exposure-response analyses, the aim of the present study was to investigate the use of PT-adjustment approaches (i.e., the use of observed individual PT measurements) to enhance the prediction of individual rivaroxaban exposure metrics (derived using a previously developed integrated population PK model) based on the observed linear relationship between PT and rivaroxaban plasma concentrations. The PT-adjustment approaches were established using time-matched PK and PT measurements, which were available from 1,779 patients across four phase II trials and one phase III trial of rivaroxaban. PT-adjusted exposure estimates improved the identification of statistically significant effects when compared with covariate-only exposure estimates.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Rivaroxabana/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Tempo de Protrombina , Rivaroxabana/farmacologiaRESUMO
Rivaroxaban (Xarelto) is an oral, direct factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. The aim was to compare the population pharmacokinetics (PK) and pharmacodynamics (PD) of twice-daily (bid) and once-daily (od) rivaroxaban in patients undergoing total hip replacement (THR). Blood samples were collected from patients enrolled in two phase IIb, dose-ranging studies undertaken to investigate rivaroxaban for thromboprophylaxis after THR. A sparse sampling technique was used and the samples were pooled for PK and PD analysis, which used non-linear mixed effect modelling. Rivaroxaban PK (samples from 758 patients) were well described by an oral, one-compartment model; age and renal function influenced clearance, and body surface area affected volume of distribution. When comparing the same total daily doses, maximum plasma concentrations of rivaroxaban were higher and minimum plasma concentrations were lower with od dosing, compared with bid dosing; however, the 90% intervals overlapped. The area under the plasma concentration-time curve was 18-30% higher in the od than in the bid study. Prothrombin time in seconds (samples from 1181 patients) correlated with rivaroxaban plasma concentrations in a linear fashion in both studies. In conclusion, the PK and PD of rivaroxaban were predictable when given either bid or od. These findings, along with the suggested efficacy and safety of rivaroxaban in the phase II studies, relative to enoxaparin, supported the selection of a convenient, once-daily 10 mg rivaroxaban dose for investigation in phase III studies.
Assuntos
Artroplastia de Quadril/métodos , Morfolinas/farmacologia , Morfolinas/farmacocinética , Tiofenos/farmacologia , Tiofenos/farmacocinética , Tromboembolia Venosa/prevenção & controle , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Método Duplo-Cego , Fator Xa/farmacocinética , Fator Xa/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Tempo de Protrombina , Rivaroxabana , Tiofenos/administração & dosagemRESUMO
BACKGROUND: There is a clinical need for novel oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. This analysis was performed to characterize the population pharmacokinetics and pharmacodynamics of rivaroxaban in patients participating in two phase II, double-blind, randomized, active-comparator-controlled studies of twice-daily rivaroxaban for the prevention of venous thromboembolism after total hip- or knee-replacement surgery. METHODS: Sparse blood samples were taken from all patients participating in the studies (n = 1009). In addition, a subset of patients in the hip study (n = 36) underwent full profiling. Rivaroxaban plasma concentrations, FXa activity and the prothrombin time were determined. Nonlinear mixed-effects modelling was used to model the population pharmacokinetics and pharmacodynamics of rivaroxaban. RESULTS: An oral one-compartment model described the population pharmacokinetics of rivaroxaban well. On the first postoperative day only, categorization of patients as slow or fast absorbers as a tool to address variability in absorption improved the fit of the model. Clearance of rivaroxaban was lower and more variable on the first postoperative day, and so time was factored into the model. Overall, the only major difference between the models for the hip study and the knee study was that clearance was 26% lower in the knee study, resulting in approximately 30% higher exposure. Residual variability in the models was moderate (37% and 34% in the hip and knee studies, respectively). Plasma concentrations of rivaroxaban increased dose dependently. Pharmacokinetic parameters that were estimated using the models agreed closely with results from full-profile patients in the hip study, demonstrating that rivaroxaban pharmacokinetics are predictable. The pharmacokinetics of rivaroxaban were affected by expected covariates: age affected clearance in the hip study only, haematocrit (on the first postoperative day only) and gender affected clearance in the knee study only, and renal function affected clearance in both studies. Bodyweight affected the volume of distribution in both studies. However, the effects of covariates on the pharmacokinetics of rivaroxaban were generally small, and predictions of 'extreme' case scenarios suggested that fixed dosing of rivaroxaban was likely to be possible. FXa activity and the prothrombin time were both affected by surgery, probably because of perioperative bleeding and intravenous administration of fluids; therefore, time was included in the pharmacodynamic models. In both studies, FXa activity correlated with rivaroxaban plasma concentrations following a maximum effect model, whereas prothrombin time prolongation correlated following a linear model with intercept. The slope of the prothrombin time prolongation correlation was 3.2 seconds/(100 microg/L) in the hip study and 4.2 seconds/(100 microg/L) in the knee study. Both pharmacodynamic models in both studies demonstrated low residual variability of approximately 10%. CONCLUSION: This population analysis in patients undergoing major orthopaedic surgery demonstrated that rivaroxaban has predictable, dose-dependent pharmacokinetics that were well described by an oral one-compartment model and affected by expected covariates. Rivaroxaban exposure could be assessed using the prothrombin time, if necessary, but not the international normalized ratio. The findings suggested that fixed dosing of rivaroxaban may be possible in patients undergoing major orthopaedic surgery.
Assuntos
Inibidores do Fator Xa , Morfolinas/farmacologia , Morfolinas/farmacocinética , Tiofenos/farmacologia , Tiofenos/farmacocinética , Tromboembolia Venosa/prevenção & controle , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Artroplastia de Quadril , Artroplastia do Joelho , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Morfolinas/administração & dosagem , Dinâmica não Linear , Tempo de Protrombina , Rivaroxabana , Fatores Sexuais , Tiofenos/administração & dosagem , Fatores de Tempo , Distribuição TecidualRESUMO
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 TempoRESUMO
The population pharmacokinetics (PK) of rivaroxaban have been evaluated in several population-specific models. We developed an integrated population PK model using pooled data from 4,918 patients in 7 clinical trials across all approved indications. Effects of gender, age, and weight on apparent clearance (CL/F) and apparent volume of distribution (V/F), renal function, and comedication on CL/F, and relative bioavailability as a function of dose (F) were analyzed. Virtual subpopulations for exposure simulations were defined by age, creatinine clearance (CrCL) and body mass index (BMI). Rivaroxaban PK were adequately described by a one-compartment disposition model with a first-order absorption rate constant. Significant effects of CrCL, use of comedications, and study population on CL/F, age, weight, and gender on V/F, and dose on F were identified. CrCL had a modest influence on exposure, whereas age and BMI had a minor influence. The model was suitable to predict rivaroxaban exposure in patient subgroups of special interest.