Mirabegron 25 mg (PR) · Tablets

Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Although mirabegron showed very low intrinsic activity for cloned human beta-1 AR and beta-2 AR, results in humans indicate that beta-1 AR stimulation occurred at a mirabegron dose of 200 mg.

Mirabegron Monotherapy for Adult OAB — After oral administration of mirabegron in healthy volunteers, mirabegron was absorbed to reach maximum plasma concentrations (Cmax) at approximately 3.5 hours. The absolute bioavailability increased from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increased more than dose proportionally. This relationship was more apparent at doses above 50 mg. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady-state concentrations were achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady-state was approximately double that seen after a single dose.

Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) — The median Tmax of mirabegron following oral administration of a single dose of mirabegron extended-release tablets in pediatric patients under fed state was 4 to 5 hours. Population pharmacokinetic analysis predicted that the median Tmax of mirabegron at steady-state was 3 to 4 hours.

Mirabegron Monotherapy for Adult OAB — There were no clinically significant differences in mirabegron pharmacokinetics when administered with or without food in adult patients.

Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) — In the fasted state, steady-state mirabegron AUC increased by 120% relative to the fed state in pediatric patients receiving mirabegron.

Mirabegron Monotherapy for Adult OAB — Mirabegron is extensively distributed in the body. The volume of distribution at steady-state (Vss) is approximately 1,670 L following intravenous administration. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. Based on an in vitro study, erythrocyte concentrations of 14C-mirabegron were about 2-fold higher than in plasma.

Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) — Mirabegron volume of distribution was relatively large in pediatric patients (the range of mean Vz/F under fed state in pediatric patients across studies: 4,895 to 13,726 L) and increased with increasing body weight.

Mirabegron Monotherapy for Adult OAB — The terminal elimination half-life (t1/2) of mirabegron is approximately 50 hours in patients.

Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) — The mean terminal elimination half-life (t1/2) of mirabegron is approximately 26 to 31 hours in pediatric patients.

Metabolism — Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14C-mirabegron. Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor. Although, in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination. In healthy subjects who were genotypically poor metabolizers of CYP2D6, mean Cmax and AUCtau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT), and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6.