mirabegron and Arrhythmias--Cardiac

Translational assessment of cardiac safety parameters is a challenge in clinical development of beta-3 adrenoceptor agonists. The preclinical tools are presented that were used for assessing human safety for mirabegron.. Studies were performed on electrical conductance at ion channels responsible for cardiac repolarization (I. In conscious dogs, mirabegron (0.01-10mg/kg, p.o.) dose-dependently increased HR, reduced SBP but DBP was unchanged. Propranolol blocked the decrease in SBP and attenuated HR increase at 100mg/kg mirabegron. Mirabegron, at 30, 60, or 100mg/kg, p.o., had no significant effect on the QT. Up to exposure levels well exceeding human clinical exposure no discernible effects on ion channel conductance or on arrhythmogenic parameters in ventricular wedge resulted for mirabegron, or its main metabolites, confirming human cardiac safety findings. In vivo, dose-related increases in HR with effects markedly higher than seen clinically, was mediated in part by cross-activation of beta-1 adrenoceptors. This non-clinical cardiac safety test program therefore proved predictive for human cardiac safety for mirabegron.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Arrhythmias, Cardiac; Blood Pressure; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Female; Heart Rate; HEK293 Cells; Humans; Male; Thiazoles; Translational Research, Biomedical

Mirabegron is a new selective β3-adrenoreceptor agonist licensed for the treatment of overactive bladder (OAB). In clinical trials, mirabegron is well-tolerated with a low side-effect profile. There is little data available on the risks in a non-selected population. The presence of β-adrenoreceptors in cardiac and vascular tissue leads to the possibility of the development of adverse cardiovascular events. We conducted a consecutive cohort study to assess the risk of developing palpitations, the severity of the condition and to investigate any underlying risk factors that predispose patients with OAB to develop palpitations whilst taking mirabegron.. A consecutive cohort of patients with OAB was studied between February 2013 and June 2014. Patients were prescribed mirabegron 50mg daily and outcomes assessed at 6 weeks. Patients with known cardiac arrhythmias were excluded. In patients who developed palpitations, a detailed account of their symptoms and medical history were documented and a 12-lead electrocardiogram (ECG) was performed to assess heart rate, QT interval and the presence of any persisting arrhythmia was conducted.. A total of 279 patients were started on mirabegron. Eight patients (2.9%) reported palpitations whilst taking the drug. Two patients with a history of palpitations with no history of prolonged QT interval or arrhythmia on ECG developed worsening palpitations. The QTc was prolonged in two patients at 0.458 and 0.441s (QTc <420). Three patients developed chest pain or tightness. The palpitations resolved once therapy was stopped and did not result in serious adverse events such as hospitalisation.. Palpitations in an unselected population have a similar incidence to that demonstrated in previous drug trials. Palpitations may be associated with a worsening of cardiovascular dysfunction.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aged; Aged, 80 and over; Arrhythmias, Cardiac; Cohort Studies; Electrocardiography; Female; Heart Rate; Humans; Middle Aged; Risk Factors; Thiazoles; Urinary Bladder, Overactive