Indications
Mirabegron is primarily indicated for the management of overactive bladder (OAB), characterized by symptoms such as urge urinary incontinence, urgency, and increased urinary frequency. It may be administered as a monotherapy or in conjunction with solifenacin. Additionally, Mirabegron is approved for treating neurogenic detrusor overactivity (NDO) in pediatric patients aged three years and older and weighing at least 35 kg.
Pharmacodynamics
The pharmacological action of Mirabegron involves the relaxation of bladder smooth muscle, thereby enhancing bladder capacity and alleviating urgency. While it does not significantly impact the mean maximum flow rate or mean detrusor pressure at maximum flow rate in patients with lower urinary tract symptoms and bladder outlet obstruction (BOO), caution is advised in patients with BOO due to potential significant urinary retention. Furthermore, Mirabegron may increase blood pressure and heart rate in a dose-dependent manner, necessitating careful use in patients with severely uncontrolled hypertension or other conditions where such increases might pose a risk.
Absorption
The oral bioavailability of Mirabegron ranges from 29% at a 25 mg dose to 35% at a 50 mg dose. The time to reach maximum plasma concentration (Tmax) is approximately 3.5 hours for both extended-release tablet and suspension formulations, whereas the granule formulation achieves Tmax in 4-5 hours. Both the maximum concentration (Cmax) and area under the curve (AUC) of the drug increase more than proportionally with dosage increments. For instance, elevating the dose from 50 mg to 100 mg results in a 2.9-fold and 2.6-fold increase in Cmax and AUC, respectively, while increasing from 50 mg to 200 mg leads to 8.4-fold and 6.5-fold increases, respectively. Steady-state concentrations are typically reached after approximately seven days of daily administration.
Metabolism
Mirabegron undergoes extensive metabolism through various pathways, although the unchanged drug remains the predominant circulating component post-oral administration. Metabolic pathways include amide hydrolysis, glucuronidation, and secondary amine oxidation or dealkylation, among others. The enzymes implicated in the oxidative metabolism of Mirabegron are likely CYP3A4 and CYP2D6, while UDP-glucuronosyltransferases such as UGT2B7, UGT1A3, and UGT1A8 are associated with conjugation reactions. Additional enzymes potentially involved in the metabolism include butyrylcholinesterase and possibly alcohol dehydrogenase.
Mechanism of Action
Mirabegron functions as an effective and selective agonist of beta-3 adrenergic receptors. By activating these receptors, it facilitates the relaxation of detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle. This action enhances the bladder's capacity to store urine, consequently reducing the sensations of urgency and frequency.
