Asunto(s)

Broncodilatadores , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Administración por Inhalación , Broncodilatadores/administración & dosificación , Broncodilatadores/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico

Asunto(s)

Broncodilatadores , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Broncodilatadores/administración & dosificación , Broncodilatadores/efectos adversos , Broncodilatadores/uso terapéutico

RESUMEN

Introduction: Revefenacin is a once-daily nebulized long-acting muscarinic antagonist (LAMA). Revefenacin is supplied as single-use nebulized vials, which may be preferable and less costly for hospital and health-system pharmacies to dispense versus multidose tiotropium inhalers. Estimates of LAMA multidose inhaler wasted doses remains unknown. Methods: This was a single-center descriptive cross-sectional study conducted between January 1 2021 and December 31 2021. Adult patients 18 years and older admitted to a 500-bed academic medical center in the southern United States and were ordered multidose tiotropium packages or single-use revefenacin vials during the study period were included. Results: Among 602 inpatients, there were 705 LAMA orders: 541 tiotropium (76.7%) and 164 revefenacin (23.3%). Four hundred ninety-five tiotropium orders (91.5%) wasted between 20% and 90% of multidose packages. Approximately $24,000 tiotropium doses were wasted versus single-use revefenacin vials. Conclusion: Multidose inhalers of tiotropium dispensed to hospitalized patients contributed to wasted doses compared to nebulized single-use revefenacin vials. Opportunities exist to minimize wasted doses of multidose long-acting inhalers dispensed to hospitalized patients.

RESUMEN

BACKGROUND: Replicate, 12-week, phase 3 trials (0126 and 0127) of once-daily nebulized revefenacin 175 µg vs placebo demonstrated significant bronchodilation and improvements in health status in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). This post hoc analysis evaluated improvement in patient-reported outcomes (PROs), including the St. George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), and Clinical COPD Questionnaire (CCQ) in both women and men. METHODS: Participants were pooled from the two 12-week studies (411 [51%] women and 401 [49%] men). Changes in PROs were assessed overall and separately in men and women. RESULTS: Revefenacin improved SGRQ and CAT total scores from baseline in both studies; improvement in CCQ total score reached significance only in 0126. In pooled data, a greater proportion of patients achieved clinically meaningful response in SGRQ score (≥4-unit decrease from baseline) with revefenacin vs placebo (odds ratio, 1.5; 95% confidence interval, 1.1-2.1; P = 0.012). Clinically meaningful responses were also seen in CAT (≥2-unit decrease from baseline) and CCQ (≥0.4-unit decrease from baseline) scores with revefenacin vs placebo. When stratified by sex, improvements from baseline in SGRQ, CAT, and CCQ scores following revefenacin vs placebo reached statistical significance only in women. CONCLUSIONS: Maintenance treatment with revefenacin improved health status in patients with moderate to very severe COPD; however, the effect was more pronounced for women than men. CLINICALTRIALS: GOV: NCT02459080; NCT02512510.

Asunto(s)

Antagonistas Muscarínicos , Enfermedad Pulmonar Obstructiva Crónica , Femenino , Humanos , Masculino , Benzamidas , Broncodilatadores/uso terapéutico , Volumen Espiratorio Forzado , Estado de Salud

RESUMEN

Background Revefenacin (REV) is a novel once-daily long-acting muscarinic antagonist (LAMA) in the treatment of moderate to very severe chronic obstructive pulmonary disease (COPD). This systematic review incorporating a dose-response meta-analysis aimed to assess the efficacy and safety of REV. Methods PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, VIP database, and Wanfang database were searched from their inception to April 2020. We included randomized controlled trials (RCTs) which evaluated the efficacy and safety of REV in COPD patients. Two reviewers independently performed study screening, data extraction, and risk of bias assessment. Outcomes consisted of the mean change in trough Forced Expiratory Volume in 1 second (FEV1) from baseline, adverse events (AEs), and serious adverse events (SAEs). A dose-response meta-analysis using the robust error meta-regression method was conducted. We used Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. Results Nine RCTs (3,121 participants) were included in this systematic review. The meta-analyses indicated that 175 µg/day REV could significantly improve the trough FEV1 (MD=143.67, 95%CI: 129.67 to 157.68; I2=96%; 809 participants; studies=4; low quality) without increasing the risk of AEs (OR=0.98, 95%CI: 0.81 to 1.18; I2=34%; 2,286 participants; studies=7; low quality) or SAEs (OR=0.89, 95%CI: 0.55 to 1.46; I2=0%; 2,318 participants; studies=7; very low quality) compared to placebo. Furthermore, the effect of REV in increasing trough FEV1 was dose-dependent with an effective threshold of 88 µg/day (R2 = 0.7017). Nevertheless, only very low-quality to low-quality evidence showed that REV at a dose of 175 µg/day was inferior to tiotropium regarding the long-term efficacy, and its safety profile was not superior to tiotropium or ipratropium. Conclusion Current evidence shows that REV is a promising option for the treatment of moderate to very severe COPD. Due to most evidence graded as low quality, further studies are required to compare the efficacy, long-term safety and cost-effectiveness between REV and other LAMAs in different populations. Clinical Trial Registration: [PROSPERO], identifier [CRD42020182793].

RESUMEN

PURPOSE: This article reviews the efficacy and safety of revefenacin, the first once-daily, long-acting muscarinic antagonist, when delivered via a standard jet nebulizer in patients with chronic obstructive pulmonary disease (COPD). SUMMARY: Revefenacin 175 µg is indicated for the maintenance treatment of patients with moderate to very severe COPD. Preclinical studies showed that revefenacin is a potent and selective antagonist with similar affinity for the different subtypes of muscarinic receptors (M1-M5). Furthermore, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose dependent and lasted longer than 24 hours, demonstrating a long duration of action. In phase 2 and 3 trials, treatment with revefenacin was demonstrated to result in statistical improvements in pulmonary function (≥100 mL, P < 0.05) vs placebo, including among patients with markers of more severe disease and those who received concomitant long-acting ß-agonists or long-acting ß-agonists together with inhaled corticosteroids. Revefenacin was also demonstrated to have efficacy similar to that of tiotropium. The clinical trial findings indicated no significant difference between revefenacin and tiotropium with regard to rates of adverse events. Overall, revefenacin was well tolerated, with COPD worsening/exacerbation, dyspnea, headache, and cough among the most common adverse events noted in the clinical trials. CONCLUSIONS: Revefenacin treatment delivered via nebulization led to improvements in lung function in patients with COPD. It was also generally well tolerated, with no major safety concerns. Revefenacin provides a viable treatment option for patients with COPD and may be a suitable alternative for those with conditions that may impair proper use of traditional handheld inhalers.

Asunto(s)

Antagonistas Muscarínicos , Enfermedad Pulmonar Obstructiva Crónica , Administración por Inhalación , Benzamidas , Broncodilatadores/uso terapéutico , Carbamatos/uso terapéutico , Humanos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico

RESUMEN

Chronic pain determines a substantial burden on individuals, employers, healthcare systems, and society. Most of the affected patients report dissatisfaction with currently available treatments. There are only a few and poor therapeutic options-some therapeutic agents are an outgrowth of drugs targeting acute pain, while others have several serious side effects. One of the primary degradative enzymes for endocannabinoids, fatty acid amide hydrolase (FAAH) attracted attention as a significant molecular target for developing new therapies for neuropsychiatric and neurological diseases, including chronic pain. Using chemical graph mining, quantitative structure-activity relationship (QSAR) modeling, and molecular docking techniques we developed a multi-step screening protocol to identify repurposable drugs as FAAH inhibitors. After screening the DrugBank database using our protocol, 273 structures were selected, with five already approved drugs, montelukast, repaglinide, revefenacin, raloxifene, and buclizine emerging as the most promising repurposable agents for treating chronic pain. Molecular docking studies indicated that the selected compounds interact with the enzyme mostly non-covalently (except for revefenacin) through shape complementarity to the large substrate-binding pocket in the active site. A molecular dynamics simulation was employed for montelukast and revealed stable interactions with the enzyme. The biological activity of the selected compounds should be further confirmed by employing in vitro and in vivo studies.

Asunto(s)

Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Broncodilatadores/administración & dosificación , Antagonistas Muscarínicos/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Broncodilatadores/farmacocinética , Ensayos Clínicos como Asunto/métodos , Quimioterapia Combinada , Humanos , Antagonistas Muscarínicos/farmacocinética , Enfermedad Pulmonar Obstructiva Crónica/metabolismo

Asunto(s)

Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Broncodilatadores/administración & dosificación , Antagonistas Muscarínicos/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Preparaciones de Acción Retardada/administración & dosificación , Quimioterapia Combinada , Humanos

RESUMEN

BACKGROUND: Revefenacin, a once-daily, long-acting muscarinic antagonist delivered via standard jet nebulizer, increased trough forced expiratory volume in 1 s (FEV1) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in prior phase 3 trials. We evaluated the efficacy of revefenacin in patients with markers of more severe COPD. METHODS: A post hoc subgroup analysis of two replicate, randomized, phase 3 trials was conducted over 12 weeks. Endpoints included least squares change from baseline in trough FEV1, St. George's Respiratory Questionnaire (SGRQ) responders, and transition dyspnea index (TDI) responders at Day 85. This analysis included patient subgroups at high risk for COPD exacerbations and compared patients who received revefenacin 175 µg and placebo: severe and very severe airflow limitation (percent predicted FEV1 30%-< 50% and < 30%), 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) D, reversibility (≥ 12% and ≥ 200 mL increase in FEV1) to short-acting bronchodilators, concurrent use of long-acting ß agonists and/or inhaled corticosteroids, older age (> 65 and > 75 years), and comorbidity risk factors. RESULTS: Revefenacin demonstrated significant improvements in FEV1 versus placebo at Day 85 among the intention-to-treat (ITT) population and all subgroups. Additionally, there was a greater number of SGRQ and TDI responders in the ITT population and the majority of subgroups analyzed among patients who received revefenacin versus placebo. For the SGRQ responders, the odds of response (odds ratio > 2.0) were significantly greater in the revefenacin arm versus the placebo arm among the severe airflow obstruction, very severe airflow obstruction and 2011 GOLD D subgroups. For the TDI responders, the odds of response (odds ratio > 2.0) were significantly greater among the severe airflow obstruction subgroup and patients aged > 75 years. CONCLUSIONS: Revefenacin showed significantly greater improvements in FEV1 versus placebo in the ITT population and all subgroups. Furthermore, there were a greater number of SGRQ and TDI responders in the ITT population, and in the majority of patient subgroups among patients who received revefenacin versus placebo. Based on the data presented, revefenacin could be a therapeutic option among patients with markers of more severe COPD. TRIAL REGISTRATION: Clinical trials registered with www.clinicaltrials.gov (Studies 0126 [NCT02459080; prospectively registered 22 May 2015] and 0127 [NCT02512510; prospectively registered 28 July 2015]).

Asunto(s)

Benzamidas/administración & dosificación , Broncodilatadores/administración & dosificación , Carbamatos/administración & dosificación , Antagonistas Muscarínicos/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Índice de Severidad de la Enfermedad , Factores de Tiempo

RESUMEN

INTRODUCTION: In chronic obstructive pulmonary disease (COPD), inhaled long-acting antimuscarinic agents (LAMA) are effective maintenance therapies used across all severity stages of the disease. Most of them are administered via dry powder inhalers, but these devices require a potent inspiratory flow which cannot be effectively achieved by patients with advanced disease. In such patients, inhaled therapy via nebulization might be an option. AREAS COVERED: Revefenacin is a LAMA that was specifically formulated for once daily nebulization and which was authorized by the FDA as a maintenance therapy for COPD. In phase II and III clinical studies discussed in this review, revefenacin demonstrated its rapid onset of action and sustained effect on lung function on both a short- and long-term basis. EXPERT OPINION: Nebulized revefenacin with once daily use does not require any particular effort of administration and hence can be used by patients with severe airways obstruction or by those having milder cognitive deficits. Further studies are needed, however, to better document the long-term cardiovascular safety and its ability to reduce the exacerbation rate.

Asunto(s)

Benzamidas/uso terapéutico , Carbamatos/uso terapéutico , Antagonistas Muscarínicos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Benzamidas/farmacocinética , Benzamidas/farmacología , Carbamatos/farmacocinética , Carbamatos/farmacología , Humanos , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacología

RESUMEN

Although no nebulized, dual mechanism, long-acting bronchodilator is currently marketed, with the approval of once-daily long-acting muscarinic antagonist (LAMA) revefenacinefenacin, it is theoretically possible to deliver a LAMA and long-acting beta2-agonist via standard jet nebulizer. The primary and secondary objectives of our study were to characterize the safety profile of revefenacin administered sequentially before or in combination with formoterol, via standard jet nebulizer in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). In this randomized, double-blind, 42-day trial (NCT03573817), patients received revenacin 175 µg (n=63) or placebo (n=59), followed by formoterol 20 µg in the morning and formoterol alone in the evening formoterol 21 days via standard jet nebulizer (sequential administration). For another 21 days, revefenacin/placebo and formoterol, were administered as mixed solutions via single nebulization in the morning (combined administration), and formoterol alone in the evening. The adverse events' (AEs) incidence was higher in the placebo + formoterol arms (11%-12%) than in the revefenacin + formoterol arms (5%-8%). The most common AEs were worsening/exacerbation of COPD, cough, and dizziness. There were no serious AEs or deaths reported in any arm. The least squares mean in trough forced expiratory volume in 1 second (FEV1) versus baseline was higher in the revefenacin + formoterol arms (116-157 mL) than in the placebo + formoterol arms (35-53 mL). Revefenacin had a safety profile similar to formoterol alone when delivered sequentially or combined. Trough FEV1 was similar when revefenacin was delivered sequentially or combined with formoterol, with revefenacin providing an additional 81-104 mL improvements over formoterol alone.

RESUMEN

Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death in the United States. Due to the substantial public health burden of COPD, there has been a lot of interest in developing new drug therapies, directed at improving the symptomatology and quality of life in COPD patients. Revefenacin is the first once daily nebulized long acting muscarinic antagonist for COPD treatment. It offers an advantage over other nebulized bronchodilators, as once daily administration may improve patient compliance. Revefenacin has a rapid onset of action, is long acting and significantly improves lung function (FEV1) in patients with COPD. It can play a major role in the management of COPD, especially in patients who have difficulty mastering inhaler techniques and those with low baseline FEV1 who may have difficulty generating flow with an inhaler. This manuscript is a review on revefenacin and outlines the pharmacologic profile and the clinical trials which have evaluated it's the efficacy and safety. The authors also discuss their own perspective on the potential role of revefenacin in COPD management.

Asunto(s)

Benzamidas/uso terapéutico , Carbamatos/uso terapéutico , Antagonistas Muscarínicos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Esquema de Medicación , Volumen Espiratorio Forzado , Humanos , Cumplimiento de la Medicación , Nebulizadores y Vaporizadores , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Resultado del Tratamiento

RESUMEN

Introduction: Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by irreversible or incompletely reversible airflow limitation. Long-acting bronchodilators, including ß2 agonists (LABA) and muscarinic antagonists (LAMA), serve as the standard of care for maintenance therapy in COPD. Individualizing therapy to optimize selection of delivery device has the potential to improve medication adherence and clinical outcomes among COPD patients.Areas covered: Revefenacin (Yupelri) is the only LAMA approved for once-daily administration via standard jet nebulizer for the maintenance therapy in patients with COPD. Revefenacin has a unique biphenyl carbamate tertiary amine structure, differing from the quaternary amine structure of previously approved LAMAs. Here we summarize the available clinical data for this new agent and discuss its potential place in the treatment of COPD.Expert opinion: Based on available clinical trial data, revefenacin appears to be an effective and safe option for long-term maintenance therapy of COPD. Revefenacin offers a once-daily option for LAMA therapy for patients who prefer or require nebulized drug delivery. The availability of this agent can allow patients to combine nebulized therapies that could improve clinical outcomes in appropriately selected patients with COPD.

Asunto(s)

Benzamidas/uso terapéutico , Carbamatos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Benzamidas/administración & dosificación , Benzamidas/metabolismo , Carbamatos/administración & dosificación , Carbamatos/metabolismo , Ensayos Clínicos como Asunto , Humanos , Nebulizadores y Vaporizadores

RESUMEN

Revefenacin is a novel once-daily, lung-selective, long-acting muscarinic antagonist developed as a nebulized inhalation solution for the maintenance treatment of chronic obstructive pulmonary disease. In a randomized, 4-way crossover study, healthy subjects received a single inhaled dose of revefenacin 175 µg (therapeutic dose), revefenacin 700 µg (supratherapeutic dose), and placebo via standard jet nebulizer, and a single oral dose of moxifloxacin 400 mg (open-label) in separate treatment periods. Electrocardiograms were recorded, and pharmacokinetic samples were collected serially after dosing. The primary end point was the placebo-corrected change from baseline QT interval corrected for heart rate using Fridericia's formula, analyzed at each postdose time. Concentration-QTc modeling was also performed. Following administration of revefenacin 175  and 700 µg, placebo-corrected change from baseline QTcF (ΔΔQTcF) values were close to 0 at all times, with the largest mean ΔΔQTcF of 1.0 millisecond (95% confidence interval [CI], -1.2 to 3.1 milliseconds) 8 hours postdose and 1.0 millisecond (95%CI, -1.1 to 3.1 milliseconds) 1 hour postdose after inhalation of revefenacin 175 and 700 µg, respectively. Revefenacin did not have a clinically meaningful effect on heart rate (within ±5 beats per minute of placebo), or PR and QRS intervals (within ±3 and ±1 milliseconds of placebo, respectively). Using concentration-QTc modeling, an effect of revefenacin > 10 milliseconds can be excluded within the observed plasma concentration range of up to ≈3 ng/mL. Both doses of revefenacin were well tolerated. These results demonstrate that revefenacin does not prolong the QT interval.

Asunto(s)

Benzamidas/farmacología , Carbamatos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Antagonistas Muscarínicos/farmacología , Adolescente , Adulto , Benzamidas/sangre , Benzamidas/farmacocinética , Carbamatos/sangre , Carbamatos/farmacocinética , Estudios Cruzados , Método Doble Ciego , Electrocardiografía/efectos de los fármacos , Femenino , Voluntarios Sanos , Humanos , Síndrome de QT Prolongado , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/sangre , Antagonistas Muscarínicos/farmacocinética , Adulto Joven

RESUMEN

Purpose: Revefenacin, a long-acting muscarinic antagonist for nebulization, has been shown to improve lung function in patients with chronic obstructive pulmonary disease. Here we report pharmacokinetic (PK) and safety results from two multicenter, open-label, single-dose trials evaluating revefenacin in subjects with severe renal impairment (NCT02578082) and moderate hepatic impairment (NCT02581592). Subjects and methods: The renal impairment trial enrolled subjects with normal renal function and severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2). The hepatic impairment trial enrolled subjects with normal hepatic function and moderate hepatic impairment (Child-Pugh class B). Subjects received a single 175-µg dose of revefenacin through nebulization. PK plasma samples and urine collections were obtained at multiple time points for 5 days following treatment; all subjects were monitored for adverse events. Results: In the renal impairment study, the maximum observed plasma revefenacin concentration (Cmax) was up to 2.3-fold higher and area under the concentration-time curve from time 0 to infinity (AUCinf) was up to 2.4-fold higher in subjects with severe renal impairment compared with those with normal renal function. For THRX-195518, the major metabolite of revefenacin, the corresponding changes in Cmax and AUCinf were 1.8- and 2.7-fold higher, respectively. In the hepatic impairment study, revefenacin Cmax and AUCinf were 1.03- and 1.18-fold higher, respectively, in subjects with moderate hepatic impairment compared with those with normal hepatic function. The corresponding changes in THRX-195518 Cmax and AUCinf were 1.5- and 2.8-fold higher, respectively. Conclusion: Systemic exposure to revefenacin increased modestly in subjects with severe renal impairment but was similar between subjects with moderate hepatic impairment and normal hepatic function. The increase in plasma exposure to THRX-195518 in subjects with severe renal or moderate hepatic impairment is unlikely to be of clinical consequence given its low antimuscarinic potency, low systemic levels after inhaled revefenacin administration, and favorable safety profile.

Asunto(s)

Benzamidas/efectos adversos , Benzamidas/farmacocinética , Carbamatos/efectos adversos , Carbamatos/farmacocinética , Insuficiencia Hepática/metabolismo , Antagonistas Muscarínicos/efectos adversos , Antagonistas Muscarínicos/farmacocinética , Insuficiencia Renal/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Índice de Severidad de la Enfermedad , Adulto Joven

RESUMEN

This article contains information on the experimental design and methods on how the safety and tolerability data concerning patients with moderate to very severe chronic obstructive pulmonary disease (COPD) were obtained. This is in addition to our original research article. [1] We have also provided information on the clinical laboratory tests that were conducted. Further interpretation and discussion of the data are demonstrated in the article "Revefenacin, a Once-daily, Lung-selective, Long-acting Muscarinic Antagonist for Nebulized Therapy: Safety and Tolerability Results of a 52-week Phase 3 Trial in Moderate to Very Severe Chronic Obstructive Pulmonary Disease." [1].

RESUMEN

BACKGROUND: Prior replicate 12-week phase 3 trials demonstrated that once-daily doses of revefenacin inhalation solution at 88 µg and 175 µg produced significant bronchodilation over 24 h post dose in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The objective was to characterize the safety profile of revefenacin 88 µg and 175 µg over 52 weeks of treatment. METHODS: In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 88 µg or 175 µg in a double-blind manner, or open-label active control tiotropium. RESULTS: Treatment-emergent adverse events (AEs) were comparable across all treatment groups (n [%] patients; revefenacin 88 µg, 272 [74.7%]; 175 µg, 242 [72.2%]; tiotropium, 275 [77.2%]). Numerically fewer COPD exacerbations (n [%] patients) were observed with revefenacin 175 µg (73 [21.8%]) than with 88 µg (107 [29.4%]) or tiotropium (100 [28.1%]). Serious AEs were comparable with revefenacin 88 µg (58 [15.9%] and tiotropium (58 [16.3%]), but were lower with revefenacin 175 µg (43 [12.8%]), and mortality was low. In patients using revefenacin 88 µg or tiotropium with a concurrent long-acting ß-agonist (LABA) product, the incidence of AEs was slightly higher than without concurrent LABA. LABA did not affect the incidence of AEs for patients who received revefenacin 175 µg. CONCLUSIONS: Revefenacin was generally well tolerated over 52 weeks of treatment, and had a safety profile that supports its use as a long-term once-daily bronchodilator for the nebulized treatment of COPD.

Asunto(s)

Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Benzamidas/uso terapéutico , Carbamatos/uso terapéutico , Antagonistas Muscarínicos/uso terapéutico , Nebulizadores y Vaporizadores/normas , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Anciano , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Broncodilatadores/uso terapéutico , Carbamatos/administración & dosificación , Carbamatos/efectos adversos , Estudios de Casos y Controles , Antagonistas Colinérgicos/uso terapéutico , Progresión de la Enfermedad , Quimioterapia Combinada , Tolerancia a Medicamentos , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Seguridad , Índice de Severidad de la Enfermedad , Bromuro de Tiotropio/uso terapéutico , Capacidad Vital/efectos de los fármacos

RESUMEN

The cardiovascular safety of revefenacin, an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive lung disease (COPD), was evaluated in phase 3 trials in patients with moderate to very severe COPD. No clinically meaningful changes in 12-lead electrocardiogram recordings were observed with up to 52 weeks of once-daily revefenacin 88 or 175 µg. In a pooled analysis of Studies 0126 and 0127, the incidence of prolonged QT interval corrected for heart rate using the Fridericia correction formula (QTcF; >450 msec) for revefenacin 88 µg (n = 23, 5.6%) and revefenacin 175 µg (n = 23, 5.9%) was similar to that for placebo (n = 22, 5.3%). In Study 0128, the incidence of prolonged QTcF was similar in the revefenacin 175 µg (n = 25, 7.7%) and tiotropium (n = 26, 7.3%) groups and lower in the revefenacin 88 µg (n = 15, 4.2%) group. There were four major adverse cardiac events (MACEs) in Study 0126 (one, two, and one in the placebo, revefenacin 88 µg, and revefenacin 175 µg groups, respectively), no MACEs in Study 0127 and 26 MACEs in Study 0128 (9, 10 and 7 in the revefenacin 88 µg, revefenacin 175 µg and tiotropium groups, respectively). In Study 0128, only one MACE was considered possibly/probably related to revefenacin (atrial fibrillation in the revefenacin 175 µg group). Thus, revefenacin may provide beneficial nebulized therapy for patients with COPD without further elevating their risk of cardiovascular events.

Asunto(s)

Benzamidas/administración & dosificación , Benzamidas/uso terapéutico , Broncodilatadores/administración & dosificación , Broncodilatadores/uso terapéutico , Carbamatos/administración & dosificación , Carbamatos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas/efectos adversos , Broncodilatadores/efectos adversos , Carbamatos/efectos adversos , Método Doble Ciego , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/administración & dosificación , Nebulizadores y Vaporizadores , Medición de Riesgo , Bromuro de Tiotropio/administración & dosificación

RESUMEN

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease characterized by progressive and persistent airflow limitation that is not fully reversible. Revefenacin is an investigational long-acting muscarinic antagonist (LAMA), in late-stage development as a nebulized inhalation solution, which has been designed to produce long-acting bronchodilation, consistent with once-daily dosing, and with a high degree of lung-selectivity. It is more selective for muscarinic type 3 (M3) than muscarinic type 2 (M2) or muscarinic type 1 (M1) receptors. Its dissociation half-life for M3 is 82 minutes and 6.9 minutes for M1, respectively. The bronchoprotective effect is seen as early as five-minute post-dose and is sustained for up to 24 hours. The estimated 24-hour potency (expressed as the concentration of dosing solution) is 45.0 mg/ml. Once-daily dose of revefenacin provided long-term improvement in trough forced expiratory volume in one second (FEV1). It improved day 28 trough FEV1 over placebo significantly (p < 0.001). M3: M2 receptor half-life is 12 compared to the other antagonists that have M3: M2 receptor half-life around 6.0. A 24-hour serial spirometry, on day 84, showed that revefenacin 88 or 175 µg was associated with significant (p <0.01) improvements in trough FEV1 at all time points compared with placebo. Revefenacin is generally well-tolerated and unlike the other anti-muscarinics, it has no systemic anti-cholinergic adverse effects.