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

INTRODUCTION: 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. METHODS: Studies were performed on electrical conductance at ion channels responsible for cardiac repolarization (IKr, IKs, Ito, INa, and ICa,L), on QT-interval, subendocardial APD90, Tpeak-end interval, and arrhythmia's in ventricular dog wedge tissue in vitro and on cardiovascular function (BP, HR, and QTc) in conscious dogs. RESULTS: 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 QTc interval. In paced dog ventricular wedge, neither mirabegron nor metabolites M5, M11, M12, M14, and M16 prolonged QT, altered transmural dispersion of repolarization, induced premature ventricular contractions, or induced ventricular tachycardia. Mirabegron nor its metabolites inhibited IKr, IKs, Ito INa, or ICa,L at clinically relevant concentrations. DISCUSSION: 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.

Effect of mirabegron on plasma gonadotropic and steroidal hormone levels in rats after two weeks of oral administration.

The effects of mirabegron on plasma gonadotropic and steroidal hormone levels in rats were investigated, when administered orally once daily for two weeks to male and female rats at doses of 10, 30, and 100 mg/kg/day, in order to elucidate a potential mechanism for findings in the reproductive system observed in toxicity studies in rats. Significantly decreased body weight gain and food consumption were observed in males and females at 100 mg/kg/day on Days 1 to 4 of dosing. A significantly prolonged estrous interval was observed in females at 100 mg/kg/day and increased liver weights were noted in females at 30 mg/kg/day or greater. No histopathological changes were observed in the pituitary gland, adrenal glands, liver, testes, epididymides, prostate, seminal vesicle, ovaries, uterus, or vagina at any dose. In males, no treatment-related changes in levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, or dihydrotestosterone (DHT) were observed at any dose. Corticosterone levels in males increased in a dose-dependent manner at 30 mg/kg/day or greater. In females, no treatment-related changes in levels of LH, FSH, prolactin, estradiol, progesterone, or corticosterone were observed at any dose in any stage of the estrous cycle. Taken together, these results suggest that mirabegron has no effect on gonadotropic or sex steroidal hormone levels in either sex at doses up to 100 mg/kg/day. In contrast, adrenocortical hormone levels were increased in males at mirabegron doses of 30 mg/kg/day or greater.