Translational science approach for assessment of cardiovascular effects and proarrhythmogenic potential of the beta-3 adrenergic agonist mirabegron

Korstanje, Cees; Suzuki, Michitaka; Yuno, Koichiro; Sato, Shuichi; Ukai, Masashi; Schneidkraut, Marlowe J.; Yan, Gan Xin

doi:10.1016/j.vascn.2017.04.008

Cited by 16 publications

(18 citation statements)

References 25 publications

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“…As neither mirabegron nor solifenacin (Astellas Pharma, data on file) blocks the rapid component of the delayed rectifier potassium current (IKr), the usual cause of drug‐related acquired long QT syndrome, sparse evaluation of QTcF was appropriate. Furthermore, thorough‐QT studies with mirabegron and solifenacin (Astellas Pharma, data on file) have previously shown that these agents do not result in clinically relevant prolongation of individual subject‐specific correction formulae (QTcI) at therapeutic monotherapy doses.…”

Section: Discussionmentioning

confidence: 99%

“…28 The CV safety findings from the SYNERGY study support and reinforce CV safety findings from other solifenacin and mirabegron combination studies that found no clinically meaningful changes in CV safety for patients receiving solifenacin and mirabegron combination therapy compared with solifenacin or mirabegron monotherapies. [16][17][18] As neither mirabegron 29 nor solifenacin (Astellas Pharma, data on file) blocks the rapid component of the delayed rectifier potassium current (IKr), the usual cause of drug-related acquired long QT syndrome, sparse evaluation of QTcF was appropriate. Furthermore, thorough-QT studies with mirabegron 30 and solifenacin (Astellas Pharma, data on file) have previously shown that these agents do not result in clinically relevant prolongation of individual subject-specific correction formulae (QTcI) at therapeutic monotherapy doses.…”

Section: Discussionmentioning

confidence: 99%

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Cardiovascular Safety of the β₃‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial

White

Chapple

Gratzke

et al. 2018

The Journal of Clinical Pharma

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There have been concerns that treatment of overactive bladder with β -adrenoceptor agonists may potentially have detrimental cardiovascular (CV) side effects. We evaluated the CV safety of mirabegron, a β -adrenoceptor agonist, alone and in combination therapy with the antimuscarinic agent solifenacin. The SYNERGY trial was a multinational, multicenter, randomized, double-blind, parallel-group, placebo and active-controlled phase 3 trial. Patients were randomized to receive solifenacin 5 mg + mirabegron 50 mg (combination 5 + 50 mg), solifenacin 5 mg + mirabegron 25 mg (combination 5 + 25 mg), solifenacin 5 mg monotherapy, mirabegron 25 mg monotherapy, mirabegron 50 mg monotherapy, or placebo for a 12-week double-blind treatment period. A total of 3398 patients were included in the study. Mean changes from baseline to the end of therapy in ECG parameters were similar across treatment groups, although there was an increase in heart rate of 1 beat/minute in the mirabegron treatment groups. There were no clinically meaningful differences in change from baseline in QTcF between monotherapies and placebo and between monotherapies and combination therapy. There were very few major CV events: 1 of 853 (0.1%) with a nonfatal myocardial infarction in the combination 5 + 25 mg group, 2 of 848 (0.2%) with a nonfatal stroke in the combination 5 + 50 mg group, and no events in the other groups. This CV safety analysis of the combination of mirabegron and solifenacin showed rates of CV events comparable with those for monotherapy treatments based on assessments of vital signs, electrocardiograms, and adjudicated CV events.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cardiovascular Safety of the β₃‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial

White

Chapple

Gratzke

et al. 2018

The Journal of Clinical Pharma

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“…However, no cases of TdP have been reported and, according to an interesting review from our group, the finding of QT prolongation >500 msec is a very rare event [42]. In dogs, at exposures 6.5-fold higher than the maximal registered human dose (MRHD), the QT interval (when adequately corrected for HR increase using Fridericia correction method, QtcF) has not displayed prolongation [44]. In analyses conducted on isolated perfused canine ventricular tissue, mirabegron has neither shown effects on potassium channels, sodium channels, or calcium channels, nor caused any delay in cell repolarization at doses ranging from 4.5-to 24.5-fold higher than the C max observed at the MRHD [48].…”

Section: Accepted Manuscriptmentioning

confidence: 93%

“…The effect was indirect, possibly owing to the release of adrenaline. Additionally, a separate nonspecific depressant effect on the contractile function of the atrium has also been demonstrated in the presence of a β1-adrenoceptor antagonist (which was not mediated by β2 or β3-adrenoceptors) [44]. The reason for this effect remains to be completely clarified.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Cardiovascular effects of antimuscarinic agents and beta3-adrenergic receptor agonist for the treatment of overactive bladder

Rosa

Baccino

Valbusa

et al. 2018

Expert Opinion on Drug Safety

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Overactive bladder (OAB) syndrome is common in the general population, particularly in elderly patients. Antimuscarinic drugs (AMs) are considered the mainstay pharmaceutical treatment of OAB whereas β3-adrenoceptor agonists, such as mirabegron, represent a good alternative. Owing to the important role of muscarinic and β3 receptors in cardiovascular (CV) tissue and to the fact that OAB patients often have CV comorbidities, the safety-profile of these drugs constitute an important challenge. Area covered: The aim of this review is to evaluate the CV effects of AMs and mirabegron in OAB. A systematic literature search from inception until December 2017 was performed on PubMed and Medline. Expert opinion: AMs are generally considered to have good CV safety profile but, however, they may cause undesirable adverse events, such as dry mouth, constipation. CV AEs are rare but noteworthy, the most common CV consequences related to the use of these drugs are constituted by an increase in HR and QT interval. Mirabegron has similar efficacy and tolerability to AMs but causes less adverse events, with either modest hypertension and modest increase in HR (<5 bpm) being the most commonly reported.

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An Exploratory Study in Healthy Male Subjects of the Mechanism of Mirabegron‐Induced Cardiovascular Effects

Gelderen

Stölzel

Meijer

et al. 2017

The Journal of Clinical Pharma

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To explore the role of β -adrenoceptors (ARs) in the heart rate response to the selective β -adrenoceptor agonist mirabegron, 12 young male volunteers received single oral doses of the nonselective β -AR antagonist propranolol (160 mg), the selective β -AR antagonist bisoprolol (10 mg), or placebo on days 1 and 5 of each period in a 3-period crossover study. On day 5, dosing was followed by a supratherapeutic dose of mirabegron (200 mg). Vital signs, impedance cardiography, and plasma renin activity were collected. Mirabegron increased heart rate and systolic blood pressure and reduced stroke volume, whereas cardiac output and diastolic blood pressure were unaffected. Mirabegron-induced changes were attenuated by propranolol and bisoprolol. The data indicate that mirabegron has a positive chronotropic effect at supratherapeutic concentrations, which is at least partly mediated by stimulation of β -AR.

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Translational science approach for assessment of cardiovascular effects and proarrhythmogenic potential of the beta-3 adrenergic agonist mirabegron

Cited by 16 publications

References 25 publications

Cardiovascular Safety of the β₃‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial

Cardiovascular Safety of the β₃‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial

Cardiovascular effects of antimuscarinic agents and beta3-adrenergic receptor agonist for the treatment of overactive bladder

An Exploratory Study in Healthy Male Subjects of the Mechanism of Mirabegron‐Induced Cardiovascular Effects

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Translational science approach for assessment of cardiovascular effects and proarrhythmogenic potential of the beta-3 adrenergic agonist mirabegron

Cited by 16 publications

References 25 publications

Cardiovascular Safety of the β3‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial

Cardiovascular Safety of the β3‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial

Cardiovascular effects of antimuscarinic agents and beta3-adrenergic receptor agonist for the treatment of overactive bladder

An Exploratory Study in Healthy Male Subjects of the Mechanism of Mirabegron‐Induced Cardiovascular Effects

Contact Info

Product

Resources

About

Cardiovascular Safety of the β₃‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial

Cardiovascular Safety of the β₃‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial