Absorption
Mirabegron Extended-Release Tablets Monotherapy for Adult OAB:
After oral administration of mirabegron in healthy volunteers, mirabegron was absorbed to reach maximum plasma concentrations (C
max) 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 C
maxand 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 C
maxand AUC
tauby approximately 2.9-and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased C
maxand AUC
tauby 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.
Effect of Food:
Mirabegron Extended-Release Tablets Monotherapy for Adult OAB:
There were no clinically significant differences in mirabegron pharmacokinetics when administered with or without food in adult patients.
Distribution
Mirabegron Extended-Release Tablets Monotherapy for Adult OAB:
Mirabegron is extensively distributed in the body. The volume of distribution at steady-state (V
ss) is approximately 1670 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 vitrostudy, erythrocyte concentrations of
14C-mirabegron were about 2-fold higher than in plasma.
Elimination
Mirabegron Extended-Release Tablets Monotherapy for Adult OAB:
The terminal elimination half-life (t
1/2) of mirabegron is approximately 50 hours in 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 vitrostudies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron,
in vivoresults indicate that these isozymes play a limited role in the overall elimination. In healthy subjects who were genotypically poor metabolizers of CYP2D6, mean C
maxand AUC
tauwere approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively.
In vitroand
ex vivostudies 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.
Excretion
Mirabegron Extended-Release Tablets Monotherapy for Adult OAB:
Total body clearance (CL
tot) from plasma is approximately 57 L/h following intravenous administration. Renal clearance (CL
R) is approximately 13 L/h, which corresponds to nearly 25% of CL
tot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary elimination of unchanged mirabegron is dose-dependent and ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of 160 mg
14C-mirabegron solution to healthy volunteers, approximately 55% of the radioactivity dose was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in urine and 0% in feces.
Specific Populations
Geriatric Patients:
The C
maxand AUC of mirabegron following multiple oral doses in elderly volunteers (≥ 65 years) were similar to those in younger volunteers (18 to 45 years)
[see Use in Specific Populations (
8.5)]
.
Gender:
Mirabegron Extended-Release Tablets Monotherapy for Adult OAB
The C
maxand AUC of mirabegron were approximately 40% to 50% higher in females than in males. When corrected for differences in body weight, the mirabegron systemic exposure was 20% to 30% higher in females compared to males.
Race:
The pharmacokinetics of mirabegron were comparable between Caucasians and African-American Blacks. Cross studies comparison showed that the exposure in Japanese subjects were higher than that in North American subjects. However, when the C
maxand AUC were normalized for dose and body weight, the difference was smaller.
Patients with Renal Impairment:
Following single-dose administration of 100 mg mirabegron in adult volunteers with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m
2as estimated by MDRD), mean mirabegron C
maxand AUC were increased by 6% and 31% relative to adult volunteers with normal renal function. In adult volunteers with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m
2), C
maxand AUC were increased by 23% and 66%, respectively. In adult volunteers with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m
2), mean C
maxand AUC values were 92% and 118% higher compared to healthy subjects with normal renal function. Mirabegron has not been studied in adult patients with End-Stage Renal Disease (ESRD) (eGFR less than 15 mL/min/1.73 m
2)
or adult patients requiring dialysis.
Patients with Hepatic Impairment:
Following single-dose administration of 100 mg mirabegron in adult volunteers with mild hepatic impairment (Child- Pugh Class A), mean mirabegron C
maxand AUC were increased by 9% and 19%, relative to adult volunteers with normal hepatic function. In adult volunteers with moderate hepatic impairment (Child-Pugh Class B), mean C
maxand AUC values were 175% and 65% higher. Mirabegron has not been studied in adult patients with severe hepatic impairment (Child-Pugh Class C).
Drug Interaction Studies
In Vitro Studies:
Effect of Other Drugs on Mirabegron
Mirabegron is transported and metabolized through multiple pathways. Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, UGT, the efflux transporter P-glycoprotein (P-gp), and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Sulfonylurea hypoglycemic agents glibenclamide (a CYP3A4 substrate), gliclazide (a CYP2C9 and CYP3A4 substrate), and tolbutamide (a CYP2C9 substrate) did not affect the
in vitrometabolism of mirabegron.
Effect of Mirabegron on Other Drugs
Studies of mirabegron using human liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron is unlikely to inhibit the metabolism of coadministered drugs metabolized by the following cytochrome P450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 because mirabegron did not inhibit the activity of these enzymes at clinically relevant concentrations. Mirabegron did not induce CYP1A2 or CYP3A. Mirabegron inhibited P-gp-mediated drug transport at high concentrations. Mirabegron is predicted not to cause clinically relevant inhibition of OCT-mediated drug transport. Mirabegron did not affect the metabolism of glibenclamide or tolbutamide.
In Vivo Studies:
Mirabegron Extended-Release Tablets Monotherapy for Adult OAB
The effect of coadministered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of coadministered drugs was studied after single and multiple doses of mirabegron. Most drug-drug interactions (DDI) were studied using mirabegron 100 mg extended-release tablets. However, interaction studies of mirabegron with metoprolol and with metformin were studied using mirabegron 160 mg immediate-release (IR) tablets.
The effect of ketoconazole, rifampicin, solifenacin succinate, tamsulosin, and metformin on systemic mirabegron exposure is shown in Figure 1.
The effect of mirabegron on metoprolol, desipramine, combined oral contraceptive-COC (ethinyl estradiol-EE, levonorgestrel-LNG), solifenacin succinate, digoxin, warfarin, tamsulosin, and metformin is shown in Figure 2.
In these studies, the largest increase in mirabegron systemic exposure was seen in the ketoconazole DDI study. As a potent CYP3A4 inhibitor, ketoconazole increased mirabegron C
maxby 45% and mirabegron AUC by 80% after multiple dose administration of 400 mg of ketoconazole for 9 days prior to the administration of a single dose of 100 mg mirabegron in 23 male and female healthy subjects.
As a moderate CYP2D6 inhibitor, mirabegron increased the systemic exposure to metoprolol and desipramine:
- Mirabegron increased the C
maxof metoprolol by 90% and metoprolol AUC by 229% after multiple doses of 160 mg mirabegron IR tablets once daily for 5 days and a single dose of 100 mg metoprolol tablet in 12 healthy male subjects administered before and concomitantly with mirabegron.
- Mirabegron increased the C
maxof desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron in 28 male and female healthy subjects.
Figures 1 and 2 show the magnitude of these interactions on the pharmacokinetic parameters and the recommendations for dose adjustment, if any:
Figure 1: The Effect of Coadministered Drugs on Exposure of Mirabegron Extended-Release Tablets
and Dose Recommendation
Fig 1 (B26f08e4 Dfe4 4a0f B6b5 E9abb495e415 02)
(1) Although no dose adjustment is recommended with solifenacin succinate or tamsulosin based on the lack of pharmacokinetic interaction, mirabegron extended-release tablets
should be administered with caution to patients taking muscarinic antagonist medications for the treatment of OAB and in patients with clinically significant BOO because of the risk of urinary retention
[see Warnings and Precautions (
5.2)]
.
Figure 2: The Effect of Mirabegron Extended-Release Tablets
on Exposure of Coadministered Medication
Fig 2 (B26f08e4 Dfe4 4a0f B6b5 E9abb495e415 03)
(1) Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when coadministered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone
[see Warnings and Precautions (
5.4) and Drug Interactions (
7.1)]
.
(2) For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be prescribed. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect
[see Drug Interactions (
7.2)]
.
(3) Warfarin was administered as a single 25 mg dose of the racemate (a mixture of R-warfarin and S-warfarin). Based on this single-dose study, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as INR and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated
[see Drug Interactions (
7.3)]
.
(4) Although no dose adjustment is recommended with solifenacin succinate or tamsulosin based on the lack of pharmacokinetic interaction, mirabegron extended-release tablets
should be administered with caution to patients taking muscarinic antagonist medications for the treatment of OAB and in BOO because of the risk of urinary retention
[see Warnings and Precautions (
5.2)]
.
Pediatric use information is approved for Astellas Pharma Global Development, Inc.'s MYRBETRIQ (mirabegron extended-release tablets). However, due to Astellas Pharma Global Development, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
