Pharmacodynamics, pharmacokinetics and safety of revefenacin (TD-4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): Results of two randomized, double-blind, phase 2 studies

Quinn, Dean; Barnes, Christopher; Yates, Wayne; Bourdet, David L.; Moran, Edmund J.; Potgieter, Peter D.; Nicholls, Andrew; Haumann, Brett; Singh, Dave

doi:10.1016/j.pupt.2017.10.003

Cited by 34 publications

(54 citation statements)

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“…Another potential limitation is that only a single dose was tested; however, accumulation of both revefenacin and THRX-195518 is minimal after repeat daily dosing, with similar C max values observed after single and repeat dosing. 7 Therefore, the findings from this study satisfy the recommendation that QT interval prolongation be tested at exposures in excess of the therapeutic range.…”

Section: Discussionsupporting

confidence: 66%

“…21 A potential limitation of this study is that it did not include patients with COPD who have a higher exposure to the metabolite THRX-195518 than healthy subjects. 6,7 Metabolite levels observed in the healthy subjects receiving the 700-µg revefenacin dose in this study were, however, in excess of those reported in patients with COPD at the therapeutic dose (175 µg) and thus represent a higher exposure than anticipated in clinical use. Another potential limitation is that only a single dose was tested; however, accumulation of both revefenacin and THRX-195518 is minimal after repeat daily dosing, with similar C max values observed after single and repeat dosing.…”

Section: Discussioncontrasting

confidence: 65%

“…24 The PK results obtained in this study are consistent with those of previous studies in COPD patients. 6,7 Inhaled revefenacin and its primary metabolite, THRX-195518, appeared rapidly in the systemic circulation in healthy subjects, with peak concentrations achieved at the first PK sampling time, 15 minutes after onset of nebulization. Plasma concentrations of revefenacin and THRX-195518 were low and decreased in a biexponential fashion after reaching C max .…”

Section: Discussionmentioning

confidence: 99%

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Revefenacin, a Long‐Acting Muscarinic Antagonist, Does Not Prolong QT Interval in Healthy Subjects: Results of a Placebo‐ and Positive‐Controlled Thorough QT Study

Borin

Barnes

Darpö³

et al. 2019

Clinical Pharm in Drug Dev

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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 ( QTcF) values were close to 0 at all times, with the largest mean QTcF 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. x

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Section: Discussionsupporting

confidence: 66%

Section: Discussioncontrasting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

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Revefenacin, a Long‐Acting Muscarinic Antagonist, Does Not Prolong QT Interval in Healthy Subjects: Results of a Placebo‐ and Positive‐Controlled Thorough QT Study

Borin

Barnes

Darpö³

et al. 2019

Clinical Pharm in Drug Dev

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“…3 Escalation to triple therapy consisting of LAMA/LABA/ICS is recommended in patients with further exacerbations and continuing symptoms. 3 Revefenacin inhalation solution is a once daily, lung-selective LAMA administered using a standard jet nebulizer, [4][5][6] which is of particular interest to patients with COPD who prefer nebulized therapies or are unable to use handheld dry powder inhalers (DPIs) or pressurized metered-dose inhalers (pMDIs). Studies have shown that a substantial proportion of patients do not use their DPIs and pMDIs appropriately with up to 92% of patients with COPD or asthma having at least one critical error in the device's use.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of revefenacin for nebulization in patients with chronic obstructive pulmonary disease taking concomitant ICS/LABA or LABA: subgroup analysis from phase III trials

Sethi

Donohue

Ferguson³

et al. 2020

Ther Adv Respir Dis

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Background: Combinations of a long-acting muscarinic receptor antagonist (LAMA), long-acting β-agonist (LABA), and inhaled corticosteroid (ICS) are used for patients with persistent chronic obstructive pulmonary disease (COPD) exacerbations on bronchodilator monotherapy. In this prespecified subgroup analysis, we assessed the efficacy and safety of the LAMA revefenacin in patients with COPD taking concomitant LABA, including ICS/LABA (LABA subgroup). Methods: Efficacy data were obtained from two 12-week, replicate, placebo-controlled trials and safety data were pooled from the 12-week and a 52-week tiotropium-controlled trial. Patients received revefenacin 175 µg or placebo in the 12-week or tiotropium 18 µg in the 52-week studies. The efficacy endpoint was least squares (LS) mean change from baseline in trough forced expiratory volume in 1 second (FEV 1 ). Clinical health outcomes were assessed using the St. George's Respiratory Questionnaire (SGRQ). Results: Revefenacin produced similar improvements from baseline in trough FEV 1 in the non-LABA and LABA subgroups [placebo-adjusted LS mean change (95% confidence interval) in day 85 trough FEV 1 , 150.9 (110.3−191.6) ml and 139.2 (82.9−195.5) ml; p < 0.0001 versus placebo]. Similar improvements were observed in SGRQ scores in the non-LABA and LABA subgroups [−3.3 (−5.4 to −1.2) and −3.4 (−6.3 to −0.6)]. Improvements in lung function and health outcomes were observed regardless of airflow obstruction severity. Revefenacin was well tolerated with more adverse events reported in the LABA than the non-LABA subgroup. Conclusions: Once daily revefenacin for nebulization can be an effective and well-tolerated treatment for patients who require concomitant use of LABA with or without ICS. ClinicalTrials.gov identifiers: NCT02512510, NCT02459080, NCT02518139The reviews of this paper are available via the supplemental material section.

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“…Patients with arthritis, impaired manual and not a quaternary ammonium compound, which means revefenacin is a different chemical class from the inhaled muscarinic antagonists available to date (e.g., glycopyrrolate bromide, tiotropium bromide [TIO], umeclidinium bromide, aclidinium, and ipratropium bromide). Revefenacin was designed to produce sustained and localized bronchodilation with minimal systemic drug exposure [9,10] and as a result, appears to have less potential for systemic antimuscarinic side effects [11].…”

Section: Introductionmentioning

confidence: 99%

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

Donohue

Kerwin

Sethi

et al. 2019

Respiratory Medicine

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A B S T R A C TBackground: 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 β-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.

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Pharmacodynamics, pharmacokinetics and safety of revefenacin (TD-4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): Results of two randomized, double-blind, phase 2 studies

Abstract: Following single or multiple nebulized-dose administration in patients with COPD, revefenacin demonstrates a rapid onset and sustained duration of bronchodilator effect over 24 h following once-daily administration, with a PK profile that is commensurate with low systemic exposure.

Cited by 34 publications

References 21 publications

Revefenacin, a Long‐Acting Muscarinic Antagonist, Does Not Prolong QT Interval in Healthy Subjects: Results of a Placebo‐ and Positive‐Controlled Thorough QT Study

Revefenacin, a Long‐Acting Muscarinic Antagonist, Does Not Prolong QT Interval in Healthy Subjects: Results of a Placebo‐ and Positive‐Controlled Thorough QT Study

Efficacy and safety of revefenacin for nebulization in patients with chronic obstructive pulmonary disease taking concomitant ICS/LABA or LABA: subgroup analysis from phase III trials

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

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