Mirabegron

Absorption

The absolute bioavailability of orally administered mirabegron ranges from 29% at a dose of 25 mg to 35% at a dose of 50 mg. The Tmax for the extended-release tablet and suspension formulations are approximately 3.5 hours, while the Tmax for the granule formulation is 4-5 hours. Both Cmax and AUC increase more than dose proportionally - an increase in dose from 50mg to 100mg results in a 2.9- and 2.6-fold increase in Cmax and AUC, respectively, whereas an increase from 50mg to 200mg results in a 8.4- and 6.5-fold increase in Cmax and AUC, respectively.
Steady-state concentrations of mirabegron are achieved after approximately 7 days of once-daily administration.

Toxicity

At doses of up to 400mg in healthy volunteers (~8x the recommended maximum), reported symptoms of overdose included palpitations and increased heart rate. Symptoms of chronic overdosage are similar in presentation and may also include a rise in systolic blood pressure. In cases of overdosage, employ standard symptomatic and supportive measures in addition to ECG monitoring.

Description

Betanis (Mirabegron) was approved in July 2011 by the Japanese Ministry of Health, Labour, and Welfare for the treatment of urgency, urinary frequency, and urinary urge urinary incontinence associated with overactive bladder (OAB). Mirabegron is synthesized by coupling 4-nitrophenethyl amine to (R)-2-hydroxy-2-phenylacetic acid. The resulting amide is reduced to an amine. The nitro group is then reduced and the resulting aniline is coupled to 2-(2-aminothiazol-4-yl) acetic acid to give mirabegron. Mirabegron has an EC₅₀ of 22 nM (intrinsic activity=0.8) for β3-AR with no detectable activity for β1- andβ2-AR (EC₅₀>10,000 nM). In an anesthetized rat rhythmic bladder contraction model in which bladder contractions are induced by saline, mirabegron at 3 mg/kg iv decreased the frequency of rhythmic bladder contraction without suppressing contraction amplitude. These data suggest that the activation of β3-AR increases bladder capacity without influencing the frequency of bladder contraction.

Description

Mirabegron, a compound with multiple functional groups, is the active ingredient of drugs used for treating an overactive bladder. It is sold under the trade names Myrbetriq and Betmiga, both marketed by Astellas Pharma (Tokyo).
Mirabegron activates the β3 adrenergic receptor in the detrusor muscle of the bladder. Activating the receptor relaxes the muscle, allowing the bladder to accommodate a greater quantity of urine.
The drug, however, is not without adverse side effects. The most common is elevated blood pressure; but there are many others, including dry mouth, susceptibility to colds, and urinary tract infection.
Although mirabegron is taken orally, one of the hazards listed in its safety data sheets (see hazard information box) is oral toxicity. But the medicine is not toxic unless the patient consumes 5–10 times the normally prescribed dosage.

The Uses of Mirabegron

Mirabegron is a selective β3-adrenoceptor agonist with EC50 of 22.4 nM.

Background

Mirabegron is a sympathomimetic beta-3 adrenergic receptor agonist used to relax the smooth muscle of the bladder in the treatment of urinary frequency and incontinence. It is unique amongst overactive bladder treatment options in that, unlike other treatments such as solifenacin and darifenacin, it lacks significant antimuscarinic activity, which is responsible both for the therapeutic effects of these medications and their broad range of adverse effects. Mirabegron has a comparatively favorable adverse effect profile as compared to other available treatment options, and its complementary mechanism to the antimuscarinics that came before it allows for its use alongside solifenacin in refractory cases.
Mirabegron first received FDA approval in 2012, under the brand name Myrbetriq, for the treatment of adults with overactive bladder. An extended-release granule formulation was subsequently granted approval in March 2021 for the treatment of pediatric patients with neurogenic detrusor overactivity. Mirabegron is also used in other jurisdictions across the globe, including Canada, the EU, and Japan.

Indications

Mirabegron is indicated for the treatment of overactive bladder (OAB) - with symptoms of urge urinary incontinence, urgency, and urinary frequency - either alone or in combination with solifenacin. It is also indicated for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 3 years of age and older and weighing 35kg or more.

What are the applications of Application

Mirabegron is a β3-AR (β3 adrenergic receptor) agonist of bladder muscles

Pharmacokinetics

Mirabegron exerts its pharmacologic effects by forcing bladder smooth muscle to relax, thereby expanding its capacity and relieving urgency. Mirabegron does not appear to adversely affect 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), but should be used with in patients with BOO due to reports of significant urinary retention. Furthermore, mirabegron increases both blood pressure and heart rate in a dose-dependent manner and should therefore be used with caution in patients with severely uncontrolled hypertension or others for whom these increases may prove dangerous.

Metabolism

Mirabegron is extensively metabolized via a number of mechanisms, although unchanged parent drug is still the major circulating component following oral administration. Presumed metabolic pathways and their resultant metabolites include amide hydrolysis (M5, M16, M17), glucuronidation (mirabegron O-glucuronide, N-glucuronide, N-carbamoylglucuronide, M12), and secondary amine oxidation or dealkylation (M8, M9, M15), amongst others. The enzymes responsible for the oxidative metabolism of mirabegron are thought to be CYP3A4 and CYP2D6, while the UDP-glucuronosyltransferases responsible for conjugation reactions have been identified as UGT2B7, UGT1A3, and UGT1A8. Other enzymes that may be involved in the metabolism of mirabegron include butylcholinesterase and possibly alcohol dehydrogenase.