RESUMO
Mavacamten is a selective, allosteric, reversible cardiac myosin inhibitor that has been developed for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). A population pharmacokinetic (PopPK) model was developed to characterize mavacamten pharmacokinetics (PK) and the variation in mavacamten exposure associated with intrinsic and extrinsic factors. Data from 12 clinical studies (phases 1, 2, and 3) were used. Evaluable participants were those who had at least one mavacamten concentration measurement with associated sampling time and dosing information. The base model included key covariates: body weight, cytochrome P450 isozyme 2C19 (CYP2C19) phenotype with respect to PK, and formulation. The final model was generated using stepwise covariate testing and refinement processes. Simulations were performed to evaluate PK: apparent clearance (CL/F); apparent central and peripheral volumes of distribution; and steady-state average, trough, and maximum concentrations. Overall, 9244 measurable PK observations from 497 participants were included. A two-compartment model structure was selected. After stepwise covariate model building and refinement, additional covariates included were: specified mavacamten dose, omeprazole or esomeprazole administration, health/disease status, estimated glomerular filtration rate, fed status, and sex. The final PopPK model accurately characterized mavacamten concentrations. At any given dose, CYP2C19 phenotype was the most influential covariate on exposure parameters (e.g., median CL/F was reduced by 72% in CYP2C19:poor metabolizers compared with the reference participant [CYP2C19:normal metabolizer]). CL/F was also approximately 16% higher in women than in men but lower in participants receiving concomitant omeprazole or esomeprazole (by 33% and 42%, respectively) than in participants not receiving such concomitant therapy.
RESUMO
Mavacamten is the first cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). The phase III EXPLORER-HCM (NCT03470545) study used a dose-titration scheme based on mavacamten exposure and echocardiographic assessment of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Using population pharmacokinetic/exposure-response modeling and simulations of virtual patients, this in silico study evaluated alternative dose-titration regimens for mavacamten, including regimens that were guided by echocardiographic measures only. Mavacamten exposure-response models for VLVOTg (efficacy) and LVEF (safety) were developed using patient data from five clinical studies and characterized using nonlinear mixed-effects models. Simulations of five echocardiography-guided regimens were performed in virtual cohorts constructed based on either expected or equal population distributions of cytochrome P450 2C19 (CYP2C19) metabolizer phenotypes. Each regimen aimed to maximize the proportions of patients who achieved a VLVOTg below 30 mm Hg while maintaining LVEF above 50% over 40 weeks and 104 weeks, respectively. The exposure-response models successfully characterized mavacamten efficacy and safety parameters. Overall, the simulated regimen with the optimal benefit-risk profile across CYP2C19 phenotypes had steps for down-titration at weeks 4 and 8 (for VLVOTg <20 mm Hg), and up-titration at week 12 (for VLVOTg ≥30 mm Hg and LVEF ≥55%), and every 12 weeks thereafter. This simulation-optimized regimen is recommended in the mavacamten US prescribing information.
RESUMO
Two open-label, Phase 1 studies assessed the effects of omeprazole (a weak to moderate cytochrome P450 [CYP] 2C19 inhibitor) and verapamil (a moderate CYP3A4 inhibitor) on the pharmacokinetics, safety, and tolerability of mavacamten. In the omeprazole study, healthy participants received mavacamten 15 mg alone or with a 31-day course of omeprazole 20 mg once daily. In the verapamil study, healthy participants received mavacamten 25 mg alone or with a 28-day course of verapamil 240 mg once daily. In the omeprazole study, 27 of 29 randomized participants completed the study. Nine participants receiving mavacamten alone were normal metabolizers (NMs) of CYP2C19 substrates, and 6 were rapid metabolizers; 8 NMs and 6 rapid metabolizers received mavacamten + omeprazole. In both studies, mavacamten showed no safety signals and was generally well tolerated. Overall mavacamten exposure (area under the plasma concentration-time curve) increased by approximately 50% with omeprazole coadministration; maximum observed concentration (Cmax ), time to Cmax , and elimination half-life were not affected appreciably. In the verapamil study, 25 of 26 randomized participants received the study drug(s) and were included in the pharmacokinetic analyses; 24 completed the study. In the pharmacokinetic population, 12 participants received mavacamten alone (11 NMs, 1 poor metabolizer) and 13 received mavacamten + verapamil (7 NMs, 4 intermediate metabolizers, 2 poor metabolizers). Following verapamil coadministration in NMs and intermediate metabolizers, mavacamten area under the plasma concentration-time curve was minimally increased (by less than 20%), and Cmax was modestly increased (by 52%). These results suggest that mavacamten can be coadministered with weak CYP2C19 and moderate CYP3A4 inhibitors.
Assuntos
Omeprazol , Verapamil , Humanos , Citocromo P-450 CYP2C19/genética , Verapamil/efeitos adversos , Voluntários Saudáveis , Interações Medicamentosas , Área Sob a CurvaRESUMO
Mavacamten is a potential inducer of cytochrome P450 (CYP) 3A4 and, as such, could reduce the exposure of the active components of oral contraceptives, ethinyl estradiol (EE) and norethindrone (NOR), where CYP3A4 is involved in metabolism. This study assessed if repeat doses of mavacamten led to a drug-drug interaction with EE and/or NOR. This was an open-label study in healthy women. In Period 1, participants received 35 mcg of EE and 1 mg of NOR. In Period 2, participants received oral loading doses of mavacamten 25 mg on Days 1-2, 15 mg/day on Days 3-17, and 35 mcg of EE and 1 mg of NOR on Day 15. Plasma concentrations of mavacamten, EE, and NOR were obtained before dosing and up to 72 hours after dosing. For EE only, a physiologically based pharmacokinetic model was used to simulate mavacamten-mediated CYP3A4 induction with EE for various CYP2C19 phenotypes. In total, 13 women were enrolled (mean age, 38.9 [standard deviation, 9.65] years). After mavacamten administration, modest increases in area under the concentration-time curves were observed for both EE and NOR. The maximum concentrations and half-lives for EE and NOR were not affected by coadministration with mavacamten. Criteria for bioequivalence were met or nearly met for EE and NOR exposure with geometric mean ratios between 0.8 and 1.25. All adverse events were mild. The physiologically based pharmacokinetic model predicted a less than 15% decrease in EE exposure across CYP2C19 phenotypes. Coadministration of mavacamten at a therapeutically relevant dose with EE and NOR did not decrease the exposure to either EE or NOR to a level that may lead to reduced effectiveness.
RESUMO
AG10 is a novel, potent, and selective oral transthyretin (TTR) stabilizer being developed to treat TTR amyloidosis (ATTR). This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics (ex vivo stabilization) of orally administered AG10 in healthy adult volunteers. Both mutant and wild-type ATTR are underdiagnosed diseases with limited therapeutic options. As TTR amyloidogenesis is initiated by dissociation of TTR tetramers destabilized due to inherited mutations or aging, AG10 is designed to treat the disease at its source. Four single and three multiple ascending dose levels of AG10 or matching placebo were orally administered. Safety and tolerability were assessed by vital signs, electrocardiogram, adverse events, and clinical laboratory tests. Pharmacokinetics were measured using a validated bioanalytical assay. Pharmacodynamics were assessed via three pharmacodynamic assays of TTR stabilization. AG10 was uniformly well tolerated, and no safety signals of clinical concern were observed. Pharmacokinetic observations included time to maximum concentration <1 hour, dose-dependent maximum concentration and area under the plasma concentration-time curve, low intersubject variability, and half-life â¼25 hr. Complete (>90%) stabilization of TTR was observed across the entire dosing interval at steady state on the highest dose tested. Serum TTR levels, an in vivo reflection of TTR stabilization by AG10, increased from baseline following 12 days of dosing. AG10 appears to be safe and well tolerated in healthy adult volunteers and can completely stabilize TTR across the dosing interval, establishing clinical proof of concept. Based on these data, AG10 has the potential to be a safe and effective treatment for patients with either mutant or wild-type ATTR.
Assuntos
Benzoatos , Pirazóis , Administração Oral , Adolescente , Adulto , Neuropatias Amiloides Familiares , Benzoatos/efeitos adversos , Benzoatos/sangue , Benzoatos/farmacocinética , Benzoatos/farmacologia , Método Duplo-Cego , Jejum/metabolismo , Feminino , Interações Alimento-Droga , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pré-Albumina/análise , Pirazóis/efeitos adversos , Pirazóis/sangue , Pirazóis/farmacocinética , Pirazóis/farmacologia , Adulto JovemRESUMO
AIMS: Voxelotor (previously GBT440) is a haemoglobin (Hb) modulator that increases Hb-oxygen affinity, thereby reducing Hb polymerization and sickling of red blood cells (RBCs), being developed as a once-daily oral drug to treat sickle cell disease (SCD). This first-in-human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of voxelotor in healthy volunteers and SCD patients. METHODS: A total of 40 healthy volunteers (100, 400, 1000, 2000 or 2800 mg) and 8 SCD patients (1000 mg) were randomly assigned to a single dose of voxelotor once daily (n = 6 per group) or placebo (n = 2 per group). Twenty-four healthy volunteers received multiple doses of voxelotor once daily for 15 days (300, 600 or 900 mg, n = 6 per group) or placebo (n = 2 per group). RESULTS: Voxelotor was well tolerated and exhibited a linear pharmacokinetic profile and a half-life ranging from 61 ± 7 h to 85 ± 7 h. High partitioning into the RBC compartment provides evidence of highly specific binding to Hb. Voxelotor exhibited a concentration-dependent left-shift of oxygen equilibrium curves. Percent Hb modification following 900 mg voxelotor for 15 days was 38 ± 9%. Terminal half-life of voxelotor in SCD patients (50 ± 3 h) was shorter than in healthy volunteers. Evaluation of erythropoietin, exercise testing, and haematologic parameters were consistent with normal oxygen delivery during both rest and exercise. CONCLUSION: This first-in-human study demonstrates voxelotor was well tolerated in SCD patients and healthy volunteers and established proof of mechanism on increasing Hb-oxygen affinity.
Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/farmacocinética , Benzaldeídos/farmacocinética , Pirazinas/farmacocinética , Pirazóis/farmacocinética , Adolescente , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/diagnóstico , Antidrepanocíticos/administração & dosagem , Antidrepanocíticos/efeitos adversos , Benzaldeídos/administração & dosagem , Benzaldeídos/efeitos adversos , Biomarcadores/sangue , Método Duplo-Cego , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Feminino , Humanos , Londres , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Oxiemoglobinas/metabolismo , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , São Francisco , Resultado do Tratamento , Adulto JovemRESUMO
New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin (Hb) for oxygen, thus inhibiting HbS polymerization and downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD, followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg per day) in patients with sickle cell anemia. The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof of concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg per day or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg per day or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg per day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased Hb and reduction in hemolysis and percentage of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. These trials were registered at www.clinicaltrials.gov as #NCT02285088 and #NCT03041909.
Assuntos
Anemia Falciforme/tratamento farmacológico , Benzaldeídos/uso terapêutico , Fármacos Hematológicos/uso terapêutico , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Adolescente , Adulto , Benzaldeídos/farmacocinética , Estudos de Casos e Controles , Estudos de Coortes , Método Duplo-Cego , Feminino , Seguimentos , Fármacos Hematológicos/farmacocinética , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Pirazinas/farmacocinética , Pirazóis/farmacocinética , Distribuição Tecidual , Adulto JovemRESUMO
The spleen tyrosine kinase (SYK) regulates immune cell activation in response to engagement of a variety of receptors, making it an intriguing target for the treatment of inflammatory and autoimmune disorders as well as certain B-cell malignancies. We have previously reported on the discovery and preclinical characterization of PRT062607, a potent and highly selective inhibitor of SYK that exhibits robust anti-inflammatory activity in a variety of animal models. Here we present data from our first human studies aimed at characterizing the pharmacokinetics (PK), pharmacodynamics (PD), and safety of PRT062607 in healthy volunteers following single and multiple oral administrations. PRT062607 demonstrated a favorable PK profile and the ability to completely inhibit SYK activity in multiple whole-blood assays. The PD half-life in the more sensitive assays was approximately 24 hours and returned to predose levels by 72 hours. Selectivity for SYK was observed at all dose levels tested. Analysis of the PK/PD relationship indicated an IC50 of 324 nM for inhibition of B-cell antigen receptor-mediated B-cell activation and 205 nM for inhibition of FcεRI-mediated basophil degranulation. PRT062607 was safe and well tolerated across the entire range of doses. Clinical PK/PD was related to in vivo anti-inflammatory activity of PRT062607 in the rat collagen-induced arthritis model, which predicts that therapeutic concentrations may be safely achieved in humans for the treatment of autoimmune disease. PRT062607 has a desirable PK profile and is capable of safely, potently, and selectively suppressing SYK kinase function in humans following once-daily oral dosing.
Assuntos
Cicloexilaminas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Baço/efeitos dos fármacos , Baço/enzimologia , Adulto , Animais , Artrite Experimental/tratamento farmacológico , Linfócitos B/efeitos dos fármacos , Teste de Degranulação de Basófilos , Cicloexilaminas/farmacocinética , Células Dendríticas/efeitos dos fármacos , Meia-Vida , Voluntários Saudáveis , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacocinética , Ratos , Receptores de Antígenos de Linfócitos B/efeitos dos fármacos , Explosão Respiratória/efeitos dos fármacos , Método Simples-CegoRESUMO
AIMS: Patients with atrial fibrillation (AF) are at increased risk of stroke. Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion. METHODS AND RESULTS: Patients with AF and more than one risk factor for stroke were randomized to one of three blinded doses of betrixaban (40, 60, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0. The primary outcome was major or clinically relevant non-major bleeding. The mean follow-up was 147 days. Among 508 patients randomized, the mean CHADS2 score was 2.2; 87% of patients had previously received vitamin K antagonist therapy. The time in therapeutic range on warfarin was 63.4%. There were one, five, five, and seven patients with a primary outcome on betrixaban 40, 60, 80 mg daily, or warfarin, respectively. The rate of the primary outcome was lowest on betrixaban 40 mg (hazard ratio compared with warfarin = 0.14, exact stratified log-rank P-value 0.04, unadjusted for multiple testing). Rates of the primary outcome with betrixaban 60 or 80 mg were more similar to those of wafarin. Two ischaemic strokes occurred, one each on betrixaban 60 and 80 mg daily. There were two vascular deaths, one each on betrixaban 40 mg and warfarin. Betrixaban was associated with higher rates of diarrhoea than warfarin. CONCLUSION: Betrixaban was well tolerated and had similar or lower rates of bleeding compared with well-controlled warfarin in patients with AF at risk for stroke.
Assuntos
Anticoagulantes/administração & dosagem , Fibrilação Atrial/complicações , Benzamidas/administração & dosagem , Piridinas/administração & dosagem , Acidente Vascular Cerebral/prevenção & controle , Varfarina/administração & dosagem , Idoso , Anticoagulantes/farmacocinética , Benzamidas/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Hemorragia/induzido quimicamente , Humanos , Masculino , Piridinas/farmacocinética , Resultado do Tratamento , Varfarina/farmacocinéticaRESUMO
OBJECTIVE: To evaluate the effects of the anticoagulant betrixaban on individual heart rate-corrected QT (QTcI). RESEARCH DESIGN AND METHODS: Ninety-six healthy adults were randomly assigned to single-dose betrixaban 80 and 140 mg (therapeutic and supratherapeutic doses, respectively), placebo, and moxifloxacin 400 mg (positive control) in a four-period crossover study. Electrocardiograms were recorded at pre-dose and post-dose hours 1, 2, 3, 4, 5, 6, 8, 12, 16 and 24. MAIN OUTCOMES MEASURES: An analysis of covariance determined the placebo-corrected, time-matched mean change from baseline QTcI at the 95% upper confidence interval (UCI; one-sided). The pre-specified clinically significant change for betrixaban-treated groups was > 10 ms (95% UCI, one-sided). Subjects were monitored for safety and tolerability. RESULTS: Mean QTcI change was < 10 ms for both betrixaban groups at all time points; expected changes were observed for moxifloxacin, establishing assay sensitivity. Correlation between betrixaban plasma concentration and QTcI duration confirmed the absence of effect on QT. CONCLUSIONS: Betrixaban at therapeutic and supratherapeutic doses did not cause clinically relevant changes in QTcI intervals or other electrocardiographic parameters. Betrixaban was well tolerated.
Assuntos
Anticoagulantes/uso terapêutico , Benzamidas/uso terapêutico , Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Síndrome do QT Longo/prevenção & controle , Piridinas/uso terapêutico , Administração Oral , Adolescente , Adulto , Antibacterianos/efeitos adversos , Anticoagulantes/efeitos adversos , Compostos Aza/efeitos adversos , Benzamidas/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Fluoroquinolonas , Humanos , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Piridinas/efeitos adversos , Quinolinas/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: We evaluated the safety, efficacy, and tolerability of elinogrel, a competitive, reversible intravenous and oral P2Y(12) inhibitor that does not require metabolic activation, in patients undergoing nonurgent percutaneous coronary intervention. METHODS AND RESULTS: In a randomized, double-blind, dose-ranging phase 2b trial, 652 patients received either 300 or 600 mg of clopidogrel pre-percutaneous coronary intervention followed by 75 mg daily or 80 or 120 mg of IV elinogrel followed by 50, 100, or 150 mg oral elinogrel twice daily. Numerous exploratory safety and efficacy end points were assessed and, as such, had no prespecified primary end point, and the study was not powered to conclusively evaluate its objectives. Thrombolysis in myocardial infarction combined bleeding was increased with elinogrel (hazard ratio, 1.98; 95% confidence interval, 1.10 to 3.57), related largely to increased bleeding requiring medical attention (elinogrel 47/408 [11.5%] versus clopidogrel 13/208 [6.3%]) and occurring primarily at the percutaneous coronary intervention access site. Efficacy end points and postprocedure cardiac enzyme were similar, but there was a nonsignificant higher frequency of periprocedural myocardial infarctions in the elinogrel arms (OR, 1.59; 95% confidence interval, 0.79 to 3.48). There was an increased incidence of dyspnea (elinogrel 50/408 [12.3%] versus clopidogrel 8/208 [3.8%]) and transaminase elevation (alanine transferase/aspartate transferase >3× the upper limit of normal; elinogrel 18/408 [4.4%] versus clopidogrel 2/208 [1.0%]) in the elinogrel arms, but there were no cases of heart block, bradycardia, hypotension, or liver failure. CONCLUSIONS: In patients undergoing nonurgent percutaneous coronary intervention and in comparison with clopidogrel, intravenous and oral elinogrel therapy did not significantly increase thrombolysis in myocardial infarction major or minor bleeding, although bleeding requiring medical attention was more common. The significance of these findings will need to be more definitively determined in future Phase 3 studies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.
Assuntos
Angioplastia Coronária com Balão , Cardiopatias/terapia , Inibidores da Agregação Plaquetária/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Quinazolinonas/administração & dosagem , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Ticlopidina/análogos & derivados , Administração Oral , Angioplastia Coronária com Balão/efeitos adversos , Angioplastia Coronária com Balão/mortalidade , Canadá , Clopidogrel , Intervalo Livre de Doença , Método Duplo-Cego , Esquema de Medicação , Europa (Continente) , Feminino , Cardiopatias/sangue , Cardiopatias/mortalidade , Hemorragia/induzido quimicamente , Humanos , Injeções Intravenosas , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Razão de Chances , Inibidores da Agregação Plaquetária/efeitos adversos , Modelos de Riscos Proporcionais , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Quinazolinonas/efeitos adversos , Receptores Purinérgicos P2Y12/metabolismo , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Sulfonamidas/efeitos adversos , Trombose/etiologia , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: KILO tested 2 novel weight-based eptifibatide dosing strategies compared with standard dosing in obese patients undergoing elective percutaneous coronary intervention (PCI). Eptifibatide dosing is weight adjusted for patients up to 121 kg. Patients above this weight receive the same maximal dose, although it is unknown if this provides adequate eptifibatide concentration or platelet inhibition. METHODS: Sixty-seven patients weighing ≥125 kg undergoing elective PCI were randomized to 1 of 3 eptifibatide dosing regimens: standard dosing using a weight of 121 kg, actual body weight (ABW)-based dosing with no upper limit, or ideal body weight (IBW)-based dosing. Boluses of 180 µg/kg were given 10 minutes apart, followed by a 2.0 µg/kg per minute infusion. Plasma eptifibatide concentrations were drawn at 12 to 18 hours after initiating the infusion. Platelet aggregation was assessed at baseline and 10 minutes after the second bolus. RESULTS: Sixty-seven patients were randomized to standard (n = 22), ABW (n = 23), or IBW (n = 22) dosing. The median (25th, 75th) steady-state plasma eptifibatide concentrations were 1,740 ng/mL (1,350, 2,350), 1,780 ng/mL (1,510, 2,350), and 1,055 ng/mL (738, 1,405), respectively (P < .001). Ten-minute median (25th, 75th) platelet aggregation units were 7 (0, 21), 2 (0, 8), and 14 (8, 20), respectively (P = .001). CONCLUSIONS: Actual body weight eptifibatide dosing leads to higher plasma concentrations and greater platelet inhibition than standard or IBW dosing in obese patients undergoing PCI. Current recommendations for eptifibatide dosing may be inadequate in patients >121 kg. Further study is warranted to define the optimal dosing of eptifibatide and other medications in obese patients.
Assuntos
Doença das Coronárias/terapia , Obesidade/complicações , Peptídeos/farmacocinética , Inibidores da Agregação Plaquetária/farmacocinética , Angioplastia Coronária com Balão , Doença das Coronárias/complicações , Relação Dose-Resposta a Droga , Eptifibatida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Peptídeos/sangue , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/sangue , StentsRESUMO
Despite current dual-antiplatelet therapy with aspirin and clopidogrel, adverse clinical events continue to occur during and after percutaneous coronary intervention (PCI). The failure of clopidogrel to provide optimal protection may be related to delayed onset of action, interpatient variability in its effect, and an insufficient level of platelet inhibition. Furthermore, the irreversible binding of clopidogrel to the P2Y(12) receptor for the life span of the platelet is associated with increased bleeding risk especially during urgent or emergency surgery. Novel antiplatelet agents are required to improve management of patients undergoing PCI. Elinogrel is a potent, direct-acting (ie, non-prodrug), selective, competitive, and reversible P2Y(12) inhibitor available in both intravenous and oral formulations. The INNOVATE-PCI study is a phase 2 randomized, double-blind, clopidogrel-controlled trial to evaluate the safety, tolerability, and preliminary efficacy of this novel antiplatelet agent in patients undergoing nonurgent PCI.
Assuntos
Angioplastia Coronária com Balão/métodos , Doença da Artéria Coronariana/terapia , Antagonistas do Receptor Purinérgico P2 , Quinazolinonas/administração & dosagem , Sulfonamidas/administração & dosagem , Ticlopidina/análogos & derivados , Administração Oral , Adolescente , Adulto , Idoso , Clopidogrel , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/metabolismo , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacocinética , Quinazolinonas/farmacocinética , Receptores Purinérgicos P2Y12 , Sulfonamidas/farmacocinética , Ticlopidina/administração & dosagem , Ticlopidina/farmacocinética , Fatores de Tempo , Resultado do Tratamento , Troponina/sangue , Adulto JovemRESUMO
Although patients aged > or =75 years represent nearly 40% of all those hospitalized with acute coronary syndromes, their enrollment in trials of therapeutic interventions has been relatively modest. Thus, scarce information exists to guide clinicians in decision-making and assessing projections of safety and efficacy for antiplatelet agents. The pathobiology of aging, including age-related changes in vascular repair and integrity, applies to patient management and offers a platform for investigation. Because older patients receive excess dosing of antithrombotic agents much more often than their younger counterparts do, initial steps toward optimized care include attention to indications, dosing, and duration of treatment. This review, representing a summary of information presented at the Fourth Annual Platelet Colloquium held in Washington, DC, in January 2009 and supplemented with recent clinical trial results, underscores an increasingly narrow safety index for antiplatelet agents in the elderly and the all-important balance of safety and efficacy--a dynamic continuum that remains paramount in quality of care. Considerations for future trial designs, registries, and analyses of existing data are highlighted to better guide clinicians toward the optimal management of this rapidly growing, high-risk group.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Ensaios Clínicos como Assunto , Inibidores da Agregação Plaquetária/uso terapêutico , Fatores Etários , Idoso , HumanosRESUMO
BACKGROUND: Inhibition of the P2Y12 ADP-receptor with oral antiplatelet agents given to patients undergoing primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is associated with improved outcomes, but this strategy is limited by the time required for maximal antiplatelet effect after administration. We examined the safety and tolerability of a novel, direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, versus placebo when administered to STEMI patients before primary PCI. METHODS: The ERASE MI trial was a pilot, phase IIA, randomized, double-blind, placebo-controlled, dose-escalation study designed to evaluate the safety and tolerability of escalating doses (10, 20, 40, and 60 mg) of elinogrel administered as a single intravenous bolus before the start of the diagnostic angiogram preceding primary PCI. Patients were randomly assigned in a 1:1 manner to either elinogrel or placebo within each dosing group; and all patients received a 600-mg clopidogrel loading dose, followed by a second 300-mg clopidogrel loading dose 4 hours after PCI. The major outcome, in-hospital bleeding, was assessed with the Thrombolysis in Myocardial Infarction and Global Strategies to Open Occluded Coronary Arteries bleeding scales. Pre-PCI corrected Thrombolysis in Myocardial Infarction frame count and ST-segment resolution were also evaluated. RESULTS: Seventy patients were randomized in the dose-escalation study, but the dose-confirmation phase was not started because the trial was prematurely terminated for administrative reasons. The incidence of bleeding events was infrequent and appeared to be similar in patients treated with all doses of elinogrel versus placebo. No differences in serious adverse events, laboratory values, corrected Thrombolysis in Myocardial Infarction frame count, or ST resolution were demonstrated between elinogrel and placebo. CONCLUSIONS: With the limitations of a small study sample size, this pilot study provided preliminary data on the feasibility and tolerability of escalating doses of a direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, as an adjunctive therapy for primary PCI for STEMI.
Assuntos
Infarto do Miocárdio/tratamento farmacológico , Preparações Farmacêuticas/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Antagonistas do Receptor Purinérgico P2 , Idoso , Angioplastia Coronária com Balão , Método Duplo-Cego , Estudos de Viabilidade , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Projetos Piloto , Receptores Purinérgicos P2Y12RESUMO
Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE). Its antithrombotic effects had not been previously tested in patients. This exploratory clinical trial in the US and Canada randomized 215 patients undergoing elective total knee replacement (TKR) in a 2:2:1 ratio to receive post-operative betrixaban 15 mg or 40 mg p.o. bid or enoxaparin 30 mg s.c. q12h, respectively, for 10-14 days. The betrixaban dosage was blinded, but enoxaparin was not. Primary efficacy outcome was the incidence of VTE, consisting of deep-vein thrombosis (DVT) on mandatory unilateral (operated leg) venography, symptomatic proximal DVT, or pulmonary embolism (PE) through Day 10-14. Safety outcomes included major and clinically significant non-major bleeds through 48 h after treatment. All efficacy and bleeding outcomes were adjudicated by a blinded independent central adjudication committee. Of 214 treated patients, 175 (82%) were evaluable for primary efficacy. VTE incidence was 14/70 (20%; 95% CI: 11, 31) for betrixaban 15 mg, 10/65 (15%; 95% CI: 8, 27) for betrixaban 40 mg, and 4/40 (10%; 95% CI: 3, 24) for enoxaparin. No bleeds were reported for betrixaban 15 mg, 2 (2.4%) clinically significant non-major bleeds with betrixaban 40 mg, and one (2.3%) major and two (4.6%) clinically significant non-major bleeds with enoxaparin. A dose- and concentration-dependent effect of betrixaban on inhibition of thrombin generation and anti-Xa levels was observed. Betrixaban demonstrated antithrombotic activity and appeared well tolerated in knee replacement patients at the doses studied.
Assuntos
Artroplastia do Joelho/efeitos adversos , Enoxaparina/uso terapêutico , Inibidores do Fator Xa , Fibrinolíticos/uso terapêutico , Embolia Pulmonar/prevenção & controle , Tromboembolia/prevenção & controle , Trombose Venosa/prevenção & controle , Administração Oral , Adulto , Idoso , Canadá , Relação Dose-Resposta a Droga , Procedimentos Cirúrgicos Eletivos , Enoxaparina/administração & dosagem , Enoxaparina/efeitos adversos , Enoxaparina/farmacocinética , Feminino , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Fibrinolíticos/farmacocinética , Hemorragia/induzido quimicamente , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/etiologia , Embolia Pulmonar/patologia , Trombina/metabolismo , Tromboembolia/etiologia , Tromboembolia/patologia , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Trombose Venosa/etiologia , Trombose Venosa/patologiaRESUMO
BACKGROUND: Previous studies of the glycoprotein IIb-IIIa inhibitor eptifibatide have included patients with moderate renal impairment (serum creatinine concentrations, 2.0-4.0 mg/dL). In these patients, adjustment of the standard infusion dose (2.0 microg/kg.min) to 1.0 microg/kg.min was recommended on empiric grounds because approximately 50% of eptifibatide is cleared renally. OBJECTIVE: The present study was designed to assess teh pharmacokinetic and pharmacodynamic properties of eptifibatide in subjects with various levels of creatinine clearance (CrCl), a parameter that is a more accurate indicator of renal function than serum creatinine concentration to determine the appropriate dose adjustment in patients with reduced renal function. A secondary objective was to determine the tolerability of eptifibatide when administered to patients with decreased renal function. METHODS: This open-label study was concluded at 3 US sites experienced in conducting similar studies. Subjects with differing renal function (normal [group 1, CrCl > 80 mL/min], mild renal impairment [group 2, CrCl 51-80 mL/min], moderate renal impairment [group 3, CrCl 30-50 mL/min], or severe renal impairment [group 4, CrCl <30 mL/min]) received a 24-hour eptifibatide infusion of 2.0 microg/kg.min (groups 1, 2, and 3) or 1.0 microg/kg.min (group 4). The primary end point was the eptifibatide steady-state plasma concentration; the secondary end points included inhibition of platelet aggregation and eptifibatide clearance, terminal plasma half-life, and area under the plasma concentration-time curve. In addition to analyses performed for each group, pharmacokinetic models were estimated and eptifibatide clearance was related to CrCl as a continuous variable by linear regression. All adverse events were recorded, with particular attention to bleeding. RESULTS: Thirty-one subjects (21 men, 10 women; mean age, 58.5 years [range, 44-73 years]; mean body weight, 81.6 kg [range, 51.5-105.1 kg]; mean height, 162.9 cm [range, 150-183 cm]) were included in the study. A strong correlation was found between eptifibatide clearance and CrCl. A tree-based analytic model indicated that the optimal discrete break point for the purpose of dose adjustment was a CrCl of 55.85 mL/min, which was rounded to 50 mL/min for practical clinical reasons. In patients with moderate or severe renal impairment (CrCl < or = 50 mL/min), clearance rates and steady-state concentrations of eptifibatide were approximately 50% lower and almost 2-fold higher, respectively, than in patients with normal renal function or mild renal impairment (CrCl > 50 mL/min). Inhibition of platelet aggregation exceeded the clinically significant threshold of 80% in all groups. Five subjects had a mild bleeding event and 4 subjects experienced mild to moderate nonbleeding events, 2 of which were considered drug-related by the investigator. None of the events required intervention. CONCLUSIONS: In this study, moderate to severe renal impairment was associated with an approximately 50% reduction in total eptifibatide clearance and a corresponding doubling of plasma eptifibatide concentration. Based on these findings, in patients with moderately or severely impaired renal function (calculated CrCl < or =50 mL/min) who are scheduled for percutaneous coronary intervention or who have non-ST-segment elevation acute coronary syndromes, it is appropriate to reduce the infusion dose of eptifibatide by 50% (from 2 to 1 microg/kg.min). Because the bolus dose(s) is (are) used to establish the initial targeted plasma eptifibatide concentrations, which are independent of clearance, and given that the volume of distribution did not correlate with renal function, no adjustment of the bolus dose(s) is required.
Assuntos
Peptídeos/farmacologia , Peptídeos/farmacocinética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Insuficiência Renal/metabolismo , Adulto , Idoso , Creatinina/metabolismo , Eptifibatida , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Peptídeos/administração & dosagem , Insuficiência Renal/fisiopatologiaRESUMO
BACKGROUND: The rationale for the combined use of glycoprotein (GP) IIb/Illa inhibitors, such as eptifibatide, and antithrombin agents, such as unfractionated heparin (UFH), in patients presenting with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) and those scheduled for percutaneous coronary intervention is based on the fact that these therapies target the complementary pathophysiologic mechanisms responsible for ischemic adverse effects. The results of a recent study indicated that the combination of eptifibatide and enoxaparin is associated with a reduced rate of ischemic adverse effects compared with the combination of eptifibatide and UFH. Therefore, the coadministration of eptifibatide with enoxaparin is an attractive option for the management of patients with NSTE ACS. OBJECTIVE: This study was designed to determine whether the substitution of enoxaparin for UFH, when coadministered with eptifibatide, affects the pharmacokinetic and pharmacodynamic properties of eptifibatide. METHODS: This open-label, crossover study was conducted at the Quintiles Clinical Pharmacology Unit (Lenexa, Kansas). Healthy subjects were sequentially treated with the GP IIb-IIIa inhibitor eptifibatide (180 microg/kg bolus + 2.0 microg/kg.min infusion) plus UFH or eptifibatide plus the low-molecular-weight heparin enoxaparin, on 2 occasions, separated by a 6- to 14-day washout period. The order of administration of the 2 regimens was random. The primary end point of the study was the steady-state plasma concentration of eptifibatide (Css); secondary end points included the inhibition of platelet aggregation, area under the plasma-concentration time curve, apparent volume of distribution, plasma elimination half-life (t 1/2), and total body eptifibatide clearance (Cl). RESULTS: A total of 14 subjects (10 men, 4 women; mean [SD] age, 53.2 [6.0]years) were enrolled. The mean (SD) Css of eptifibatide was essentially identical when it was coadministered with either UFH or enoxaparin (1640 [227] ng/mL and 1610 (229) ng/mL, respectively). In addition, no clinically significant differences were found between the coadministration of UFH versus enoxaparin in platelet aggregation inhibition, t 1/2, eptifibatide Cl, or other pharmacokinetic parameters. Both regimens were well tolerated; no serious adverse effects were reported. CONCLUSION: The results in this population of healthy subjects, age-matched to the intended target population, suggest that eptifibatide can be used in the treatment of NSTE ACS effectively, with good tolerability, and without dose adjustment when coadministered with enoxaparin instead of with UFH.
Assuntos
Heparina/farmacologia , Peptídeos/farmacocinética , Inibidores da Agregação Plaquetária/farmacocinética , Trombina/antagonistas & inibidores , Idoso , Área Sob a Curva , Cromatografia Líquida , Estudos Cross-Over , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eptifibatida , Feminino , Meia-Vida , Heparina de Baixo Peso Molecular/farmacologia , Humanos , Injeções Intravenosas , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Peptídeos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Fatores de TempoRESUMO
BACKGROUND: The relative anti-aggregatory effects of currently prescribed platelet glycoprotein IIb/IIIa receptor antagonists during and after percutaneous coronary intervention for acute coronary syndromes have not been established. METHODS AND RESULTS: We randomized 70 acute coronary syndrome patients undergoing percutaneous coronary intervention to receive abciximab, eptifibatide, or tirofiban at doses used in the Evaluation of Platelet IIb/IIIa Inhibitor for STENTing (EPISTENT), Platelet glycoprotein IIb/IIIa in Unstable angina Receptor Suppression Using Integrilin Therapy (PURSUIT), and Platelet Receptor Inhibition in ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms (PRISM-PLUS)/Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) trials, respectively. Platelet aggregation (PA) in response to 20 micro mol/L of adenosine diphosphate was measured with turbidimetric aggregometry in both D-phenylalanyl-L-prolyl-L-arginine chloromethylketone and citrate-anticoagulated blood early (15 and 30 minutes) and late (4, 12, and 18 to 24 hours) after drug initiation. At 15 and 30 minutes, PA was significantly less inhibited by the tirofiban-RESTORE regimen compared with abciximab (P=0.028) and eptifibatide regimens (P=0.0001). The abciximab regimen, however, showed increasingly varied anti-aggregatory effects during continued infusion for > or =4 hours. Citrate exaggerated ex vivo platelet inhibition after eptifibatide and tirofiban, but had the opposite effect on abciximab. Of all regimens evaluated, the eptifibatide regimen inhibited PA most consistently throughout both the early and late periods. CONCLUSIONS: Currently recommended drug regimens to inhibit the platelet glycoprotein IIb/IIIa receptor have distinct pharmacodynamic profiles that might affect their relative efficacy in acute coronary syndromes and percutaneous coronary intervention.