Indications
Vibegron is approved for the treatment of overactive bladder (OAB) in adults experiencing symptoms such as urge urinary incontinence, urgency, and increased urinary frequency.
Pharmacodynamics
Vibegron exhibits high selectivity for beta-3 adrenergic receptors, with a preference exceeding 9000-fold over β1 and β2 adrenergic receptors. This selectivity allows Vibegron to effectively enhance bladder capacity without impacting bladder contraction. In clinical settings, it has been observed to increase functional bladder volume in a dose-dependent manner, thereby extending the interval between urinations. Moreover, vibegron has been shown to inhibit detrusor muscle contractions in a concentration-dependent manner, reduce voiding pressure, and improve bladder compliance. Clinical trials conducted in Japan involving patients with overactive bladder demonstrated significant improvements in the frequency of micturition, urgency, and episodes of urgency incontinence.
Absorption
Vibegron reaches peak plasma concentrations typically between 1 to 3 hours post-administration. Steady-state concentrations of the drug are achieved within seven days with once-daily dosing.
Metabolism
In vitro studies identify CYP3A4 as the primary enzyme responsible for the metabolism of vibegron, although it has a minimal role in the drug's elimination. The major metabolic pathways include oxidation and glucuronidation, leading to the formation of two oxidative metabolites and three glucuronide metabolites. However, these metabolites have not been fully characterized.
Mechanism of Action
Vibegron operates as a selective agonist of beta-3 adrenergic receptors (β3ARs), which are predominantly expressed in the urinary tract, including the bladder, urethra, ureters, prostate, and kidneys. Overactive bladder, characterized by symptoms such as urge urinary incontinence, urgency, and increased urinary frequency, results from disrupted sensory communication between the bladder, spinal cord, and brain, causing aberrant sensations and premature urges to void. Vibegron's mechanism involves binding to β3ARs, which induces a conformational change and stimulates adenylyl cyclase activity, leading to the production of cyclic adenosine monophosphate (cAMP). Elevated cAMP levels activate protein kinase A (PKA), which phosphorylates myosin light chains, inhibiting the actin-myosin interaction mediated by the calcium-calmodulin complex. Clinical studies have demonstrated that vibegron enhances cAMP concentration dose-dependently. Additionally, there is evidence suggesting that β3AR agonists like vibegron may exert effects through sensory pathways without directly influencing detrusor muscle motor function.
