Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder

Abstract

Although the physiologic role of muscarinic receptors in bladder function and the therapeutic efficacy of muscarinic antagonists for the treatment of overactive bladder are well established, the role of β-adrenergic receptors (βARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel βAR agonist vibegron (MK-4618, KRP-114V) and explored mechanistic interactions of βAR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full βAR agonist across species, and it dose dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys. The relaxation effect of vibegron was enhanced when combined with muscarinic antagonists, but differentially influenced by muscarinic receptor subtype selectivity. The effect was greater when vibegron was co-administered with tolterodine, a nonselective antagonist, compared with coadministration with darifenacin, a selective M3 antagonist. Furthermore, a synergistic effect for bladder strip relaxation was observed with the combination of a βAR agonist and tolterodine in contrast to simple additivity with darifenacin. To determine expression in rhesus bladder, we employed a novel βAR agonist probe, [H]MRL-037, that selectively labels β receptors in both urothelium and detrusor smooth muscle. Vibegron administration caused a dose-dependent increase in circulating glycerol and fatty acid levels in rhesus and rat in vivo, suggesting these circulating lipids can be surrogate biomarkers. The translation of our observation to the clinic has yet to be determined, but the combination of βAR agonists with M2/M3 antimuscarinics has the potential to redefine the standard of care for the pharmacological treatment of overactive bladder.

Effects of combined treatment with fesoterodine and mirabegron in a pelvic congestion rat model: Results from in vitro and in vivo functional studies

“…The potential synergistic effects of combined administration of 5‐HMT with mirabegron might therefore involve the restoration of mirabegron's effects by 5‐HMT. A similar result was reported with the combination of a β 3 agonist (vibegron) and a nonselective antimuscarinic agent (tolterodine) . The increase in BC was greater when vibegron was coadministered with tolterodine compared to coadministration with darifenacin, a selective M3 antagonist, in rhesus monkeys.…”

The β3‐adrenoceptor agonist mirabegron increases human atrial force through β1‐adrenoceptors: an indirect mechanism?

“…Our evidence supports previous research showing that β 3 ‐adrenoceptors do not modulate contractility of human hearts. The development of other selective β 3 ‐adrenoceptor agonists, vibegron (Di Salvo et al, ), ritobegron and solabegron (Michel and Korstanje, ), motivated by the identity of the β 3 ‐adrenoceptor as a therapeutic target to manage overactive bladder syndrome, provides further opportunities to investigate human heart β 3 ‐adrenoceptor function. Our studies may be helpful for the design and testing of future β 3 ‐adrenoceptor agonists intended for clinical use.…”

The efficacy and safety of Vibegron in treating overactive bladder: A systematic review and pooled analysis of randomized controlled trials

“…The mean half‐life of Mirabegron was around 40 hours, which is administered as a once‐daily formulation 7 . Vibegron is a novel, potent, and selective β3‐adrenergic receptor agonist and displays pharmacological activity in vitro and in vivo 8 . Several preclinical and clinical pharmacokinetic, pharmacodynamic, and toxicological profiles of Vibegron show its clinical development as an OAB medication.…”

“…Several preclinical and clinical pharmacokinetic, pharmacodynamic, and toxicological profiles of Vibegron show its clinical development as an OAB medication. Vibegron has a long half‐life (25‐38 hours), permitting a once‐daily formulation 8 …”