RESUMEN
AIMS: To explore the effect of food intake on the relative bioavailability of R1663 and on its pharmacodynamic effects (prothrombin time (PT) and activated partial thromboplastin time (aPTT)) after a single oral dose of 200 mg. METHODS: This was a prospective, open-label, randomized, two-way crossover study. Eight healthy male volunteers received R1663 on two occasions, after a high fat/high calorie breakfast and after an overnight fast of 10 h, with a 7-day washout between doses. Blood was sampled up to 48 h for the pharmacokinetic and pharmacodynamic evaluation of R1663. Pharmacokinetic parameters (area under the plasma concentration-time curve from Time 0 extrapolated to infinity (AUC(0-∞)) and maximal concentration (C(max)) as well as pharmacodynamic parameters (area under the effect curve over 48 h (AUE(0-48)) and maximal effect (E(max)) were determined on both occasions. Geometric mean ratios fed/ fasted (GMR) and 90% confidence intervals (CI) were calculated for AUC(0-∞) and C(max) of R1663 and AUE(0-48) and E(max) of PT and aPTT. RESULTS: Following food intake, C(max) was reduced by 10% with CI extended outside the bioequivalence range (GMR, 0.90; CI 0.72 - 1.13). R1663 t(max) was delayed in the fed state (4 h) as compared to the fasted state (1 h). There was no significant food effect on R1663 AUC(0-∞) (GMR, 1.09; CI 0.97 - 1.24). Although the Emax of PT showed statistically significant reduction with food, the 90% CIs for Emax and AUE(0-48) of PT and aPTT were all contained within the bioequivalence range (0.80 - 1.25). CONCLUSIONS: These findings will allow the administration of R1663 without regard to food in the upcoming trials.
Asunto(s)
Inhibidores del Factor Xa , Interacciones Alimento-Droga , Piridonas/farmacología , Piridonas/farmacocinética , Pirrolidinas/farmacología , Pirrolidinas/farmacocinética , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Dieta Alta en Grasa , Ingestión de Energía , Ayuno , Humanos , Masculino , Tiempo de Tromboplastina Parcial/estadística & datos numéricos , Tiempo de Protrombina/estadística & datos numéricos , Piridonas/efectos adversos , Pirrolidinas/efectos adversosRESUMEN
This study investigated the safety, pharmacokinetics and pharmacodynamics of multiple oral doses of R1663, a factor Xa inhibitor, and explored the influence of age and gender on pharmacokinetics and pharmacodynamics of R1663. This was a single-blind, randomised, placebo-controlled, dose escalation study in 48 healthy male volunteers aged 18 to 44 years. R1663 doses up to 300 mg twice daily or 400 mg once daily were administered for seven days. The exploration of gender and age effect was carried out in separate cohorts of eight male and eight female volunteers aged 45 to 65 years. Multiple oral doses of R1663 were safe and well tolerated. Pharmacokinetics was linear and showed moderate variability. Plasma concentrations peaked at 3 hour. Terminal half-life at steady state was 3-5 hours. Accumulation of R1663 was minimal. R1663 prolonged clotting times, inhibited thrombin generation (peak height and endogenous thrombin potential [ETP]) and anti-factor Xa activity in a concentration-dependent manner without increasing bleeding time. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations. The inhibition was more pronounced on peak height (IC50 = 194 ng/ml) than on ETP (2790 ng/ml). Pharmacokinetics and pharmacodynamics of R1663 appeared not to be substantially affected by age or gender but remained to be confirmed in larger clinical trials including older patients. Meanwhile, dose adjustments based on age and gender are not anticipated.
Asunto(s)
Inhibidores del Factor Xa , Piridonas/administración & dosificación , Piridonas/farmacocinética , Pirrolidinas/administración & dosificación , Pirrolidinas/farmacocinética , Adolescente , Adulto , Factores de Edad , Anciano , Pruebas de Coagulación Sanguínea , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piridonas/efectos adversos , Pirrolidinas/efectos adversos , Factores Sexuales , Adulto JovenRESUMEN
This study investigated the safety, pharmacokinetics, and pharmacodynamics of single oral doses of R1663, a factor Xa inhibitor, in healthy volunteers. It was a single-blind, randomized, crossover, placebo-controlled, dose escalation study in 33 healthy male volunteers aged 18 to 45 years. Each volunteer was dosed on 3 occasions with R1663 or placebo. Single oral doses of R1663 were safe and well tolerated. R1663 did not affect bleeding time. Pharmacodynamic effects (prothrombin time [PT], activated partial thromboplastin time [aPTT]), parameters of thrombogram, and anti-factor Xa activity) and plasma concentrations of R1663 were dose-dependent and showed low to moderate (<40%) intersubject and intrasubject variability. Maximum factor Xa inhibition was achieved 3 hours post dose (time to maximum concentration of R1663): clotting times were prolonged up to 2.5-fold, whereas endogenous thrombin potential (ETP) and peak height were decreased by 48% and 85% from their baseline values, respectively. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations, with IC50 values of 182 and 2680 ng/mL for peak height and ETP, respectively. Oral doses of R1663 up to 480 mg were well tolerated, with predictable pharmacodynamics and pharmacokinetics. R1663 prolonged clotting times (PT, aPTT) and inhibited thrombin generation without increasing bleeding time.
Asunto(s)
Anticoagulantes/farmacología , Inhibidores del Factor Xa , Piridonas/farmacología , Pirrolidinas/farmacología , Trombina/antagonistas & inhibidores , Administración Oral , Adolescente , Adulto , Anticoagulantes/efectos adversos , Anticoagulantes/farmacocinética , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Masculino , Persona de Mediana Edad , Tiempo de Tromboplastina Parcial , Tiempo de Protrombina , Piridonas/efectos adversos , Piridonas/farmacocinética , Pirrolidinas/efectos adversos , Pirrolidinas/farmacocinética , Método Simple Ciego , Factores de Tiempo , Adulto JovenRESUMEN
This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for C.E.R.A., a continuous erythropoietin receptor activator. C.E.R.A. is administered via intravenous (IV) and subcutaneous (SC) routes once every 2 weeks (Q2W) or once every 4 weeks (Q4W), respectively, to correct or maintain hemoglobin levels in chronic kidney disease (CKD) patients. Population models were specified to describe C.E.R.A. (PK) and hemoglobin (PD) concentrations over time, using data from 3 phase III, open-label, randomized, parallel-group, multicenter studies that examined IV or SC C.E.R.A. administration Q2W and Q4W in erythropoiesis-stimulating agent (ESA)-naive and ESA-treated patients. C.E.R.A. PK was described by a 1-compartment model: drug clearance = 0.75 L/d, volume of distribution = 4.72 L, and half-life = 105 hours in accordance with previous reported values. The PD model, a life span sequential PK/PD model, adequately described hemoglobin data. Dosing schedule, administration route, and study type did not affect drug-related PD parameters or system-specific parameters (eg, red blood cell life span). This model adequately described C.E.R.A.'s PK and PD properties according to C.E.R.A. posology, thus permitting simulations exploring alternative drug administration scenarios. It supports use of C.E.R.A. IV and SC; Q2W for anemia correction in ESA-Naïve CKD patients and monthly administration in the hemoglobin maintenance phase.
Asunto(s)
Anemia/tratamiento farmacológico , Eritropoyetina/farmacología , Hemoglobinas/efectos de los fármacos , Modelos Biológicos , Polietilenglicoles/farmacología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia/etiología , Ensayos Clínicos Fase III como Asunto , Simulación por Computador , Esquema de Medicación , Eritropoyesis/efectos de los fármacos , Eritropoyetina/administración & dosificación , Eritropoyetina/farmacocinética , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes , Factores de Tiempo , Distribución Tisular , Adulto JovenRESUMEN
AIM: To examine the effect of severe hepatic impairment (HI) on the pharmacokinetics (PK) and pharmacodynamics (PD) of the continuous erythropoietin receptor activator, C.E.R.A. METHODS: A non-randomised, multicentre, single-dose, open-label study in patients with HI (n=12) and healthy subjects (n=12). After 2 weeks of screening, participants received a single intravenous dose of C.E.R.A. (200 mug), and were then followed for approximately 8 weeks. The area under the concentration-time curve (AUC) from drug administration to last measurable concentration (AUC(last)), and maximum C.E.R.A. concentration (C(max)) were calculated to assess PK. The baseline-corrected area under the effect curve over 22 days (AUE(corr)) for reticulocyte count was the primary PD parameter. RESULTS: The PK profile was similar in patients and healthy subjects (AUC(last): 6678 vs 6985 ng*h/mL; C(max): 63 vs 75 ng/mL) C.E.R.A. produced a sustained erythropoietic response in bothgroups, with increases in reticulocyte counts peaking 7-9 days post-dose and returning to baseline by Day 22. Although mean AUE(corr) was 64% lower in patients, this may have been an artefact of higher baseline reticulocyte counts. Lower reticulocyte responses in patients did not translate into lower responses for haemoglobin, haematocrit or erythrocytes, suggesting that HI had no clinically relevant effect on the PD of C.E.R.A. C.E.R.A. was well tolerated. Four AEs (none considered drug related) were reported in three patients (mild myocardial ischaemia; mild pyrexia and liver transplant; severe bacterial peritonitis [serious AE]); no AEs were reported in healthy subjects. CONCLUSIONS: Severe HI has no clinically relevant effect on PK parameters or haematological response after single-dose C.E.R.A.
Asunto(s)
Eritropoyesis/efectos de los fármacos , Eritropoyetina/farmacocinética , Hematínicos/farmacocinética , Cirrosis Hepática/metabolismo , Polietilenglicoles/farmacocinética , Adolescente , Adulto , Anciano , Eritropoyetina/farmacología , Femenino , Hematínicos/farmacología , Humanos , Masculino , Persona de Mediana Edad , Polietilenglicoles/farmacología , Proteínas Recombinantes , Reticulocitos/efectos de los fármacosRESUMEN
OBJECTIVE: This study assessed injection site pain following subcutaneous (SC) administration with a continuous erythropoietin receptor activator (C.E.R.A.), compared with darbepoetin alfa in healthy adults. METHODS: In a randomized, placebo-controlled, single-centre, single-blind, three-way crossover study, subjects received one of six treatment sequences (ABC/ACB/BAC/BCA/CBA/CAB) involving SC injection of (A) C.E.R.A. 50 microg, (B) darbepoetin alfa 50 microg, or (C) placebo on days 1, 29, and 57. An initial pilot phase (n = 12) was used to determine the sample size for the confirmatory phase (n = 72), and data were combined for the final analysis (n = 84). MAIN OUTCOME MEASURES: The primary endpoint was pain on the 100 mm visual analog scale (VAS) immediately after dosing. Secondary endpoints included VAS at 1 hour after dosing and pain on the six-point verbal rating scale (VRS) immediately and at 1 hour after dosing. RESULTS: C.E.R.A. was associated with significantly less pain immediately after SC injection compared with darbepoetin alfa: least squares mean VAS 21.5 (95% confidence interval [CI]: 17.5, 25.5) versus 33.4 (95% CI: 28.4, 38.4) (p < 0.0001). Incidence of pain on the VRS was lower with C.E.R.A. compared with darbepoetin alfa immediately after dosing (p < 0.0001). One hour after administration, most subjects had no VRS pain. A study limitation is the small sample size and the findings need to be confirmed in a large trial of chronic kidney disease patients. CONCLUSIONS: SC injection with C.E.R.A. is significantly less painful than SC darbepoetin alfa in healthy adults. Treatment of anemia in chronic kidney disease with SC injection of C.E.R.A. may provide a lower pain burden compared with darbepoetin alfa.
Asunto(s)
Eritropoyetina/análogos & derivados , Hematínicos/administración & dosificación , Hematínicos/efectos adversos , Dolor , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Adolescente , Adulto , Anciano , Darbepoetina alfa , Eritropoyetina/administración & dosificación , Eritropoyetina/efectos adversos , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Dolor/diagnóstico , Dolor/etiología , Dimensión del Dolor , Placebos , Proteínas RecombinantesRESUMEN
C.E.R.A. (methoxy polyethylene glycol-epoetin beta), a continuous erythropoietin receptor activator, differs from traditional erythropoiesis-stimulating agents in its pharmacokinetic and receptor binding properties. This phase I, randomized, open-label, single-center, single-dose, 3-way crossover study in 42 healthy volunteers compared the pharmacokinetic and pharmacodynamic profile of C.E.R.A. 3.0 microg/kg after subcutaneous injection into the abdomen, arm, or thigh. The pharmacokinetic profile was similar at all 3 injection sites, with a prolonged apparent elimination half-life from 160 to 164 hours, area under the concentration-time curve from 4088 to 4323 ng.h/mL, and clearance/bioavailability from 0.64 to 0.68 mL/h/kg. C.E.R.A. produced a sustained erythropoietic response, and the pharmacodynamic profile (area under the reticulocyte count-time curve and maximum increase in reticulocyte count) was similar for all sites. C.E.R.A. was generally well tolerated, regardless of the administration site. This study suggests that C.E.R.A. has the potential to offer a choice of injection sites in clinical practice. The long half-life may permit effective anemia management with extended dosing intervals. Phase III clinical studies support the role of C.E.R.A. in managing anemia in patients with chronic kidney disease.
Asunto(s)
Portadores de Fármacos/farmacocinética , Eritropoyetina/farmacocinética , Polietilenglicoles/farmacocinética , Adolescente , Adulto , Anciano , Anemia/complicaciones , Anemia/tratamiento farmacológico , Enfermedad Crónica , Estudios Cruzados , Femenino , Humanos , Inyecciones Subcutáneas , Enfermedades Renales/complicaciones , Enfermedades Renales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Proteínas RecombinantesRESUMEN
Continuous Erythropoietin Receptor Activator (C.E.R.A.) is a new agent that is in development for the treatment of anemia with extended administration intervals in patients who have chronic kidney disease (CKD), both those on and those not on dialysis. This was an open-label, randomized, multicenter, two-period, crossover study in erythropoiesis-stimulating agentnaïve patients who had CKD and anemia and were receiving peritoneal dialysis. After a 1-wk run-in period, 16 patients were randomly assigned to receive a single administration of intravenous C.E.R.A. 0.4 microg/kg (n = 8) or subcutaneous C.E.R.A. 0.8 microg/kg (n = 8). Six weeks after the first administration of C.E.R.A. (4-wk assessment, 2-wk washout), the route of administration was switched so that all patients received single administrations of both intravenous C.E.R.A. 0.4 microg/kg and subcutaneous C.E.R.A. 0.8 microg/kg. C.E.R.A. had a prolonged and comparable half-life after intravenous (mean 134 h) and subcutaneous (mean 139 h) administration. Reticulocyte counts peaked at a median of 8 d after intravenous and subcutaneous administration with no difference in the time course between administration routes. This resulted in similar mean values for the area under the reticulocyte count-time curve (1191 x 10(9) and 1193 x 10(9).d per L, respectively) and the maximum absolute increase in reticulocyte counts (36 x 10(9) and 41 x 10(9)/L, respectively). C.E.R.A. has a prolonged and comparable half-life after intravenous or subcutaneous injection, suggesting that extended administration intervals may be feasible in patients with CKD.