Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Astellas Pharma Europe B.V., Sylviusweg 62, 2333 BE Leiden, The Netherlands
Pharmacotherapeutic group: Urologicals, drugs for urinary frequency and incontinence
ATC code: G04BD12
Mirabegron is a potent and selective beta3-adrenoceptor agonist. Mirabegron showed relaxation of bladder smooth muscle in rat and human isolated tissue, increased cyclic adenosine monophosphate (cAMP) concentrations in rat bladder tissue and showed a bladder relaxant effect in rat urinary bladder function models. Mirabegron increased mean voided volume per micturition and decreased the frequency of non-voiding contractions, without affecting voiding pressure, or residual urine in rat models of bladder overactivity. In a monkey model, mirabegron showed decreased voiding frequency. These results indicate that mirabegron enhances urine storage function by stimulating beta3-adrenoceptors in the bladder.
During the urine storage phase, when urine accumulates in the bladder, sympathetic nerve stimulation predominates. Noradrenaline is released from nerve terminals, leading predominantly to beta adrenoceptor activation in the bladder musculature, and hence bladder smooth muscle relaxation. During the urine voiding phase, the bladder is predominantly under parasympathetic nervous system control. Acetylcholine, released from pelvic nerve terminals, stimulates cholinergic M2 and M3 receptors, inducing bladder contraction. The activation of the M2 pathway also inhibits beta3-adrenoceptor induced increases in cAMP. Therefore, beta3-adrenoceptor stimulation should not interfere with the voiding process. This was confirmed in rats with partial urethral obstruction, where mirabegron decreased the frequency of non-voiding contractions without affecting the voided volume per micturition, voiding pressure, or residual urine volume.
Betmiga at doses of 50 mg and 100 mg once daily for 12 weeks in men with lower urinary tract symptoms (LUTS) and bladder outlet obstruction (BOO) showed no effect on cystometry parameters and was safe and well tolerated. The effects of mirabegron on maximum flow rate and detrusor pressure at maximum flow rate were assessed in this urodynamic study consisting of 200 male patients with LUTS and BOO. Administration of mirabegron at doses of 50 mg and 100 mg once daily for 12 weeks did not adversely affect the maximum flow rate or detrusor pressure at maximum flow rate. In this study in male patients with LUTS/BOO, the adjusted mean (SE) change from baseline to end of treatment in post void residual volume (ml) was 0.55 (10.702), 17.89 (10.190), 30.77 (10.598) for the placebo, mirabegron 50 mg and mirabegron 100 mg treatment groups.
Betmiga at doses of 50 mg or 100 mg had no effect on the QT interval individually corrected for heart rate (QTcI interval) when evaluated either by sex or by the overall group.
A thorough QT (TQT) study (n=164 healthy male and n=153 healthy female volunteers with a mean age of 33 years) evaluated the effect of repeat oral dosing of mirabegron at the indicated dose (50 mg once daily) and two supra-therapeutic doses (100 and 200 mg once daily) on the QTcI interval. The supra-therapeutic doses represent approximately 2.6- and 6.5-fold the exposure of the therapeutic dose, respectively. A single 400 mg dose of moxifloxacin was used as a positive control. Each dose level of mirabegron and moxifloxacin was evaluated in separate treatment arms each including placebo-control (parallel cross-over design). For both males and females administered mirabegron at 50 mg and 100 mg, the upper bound of the one-sided 95% confidence interval did not exceed 10 msec at any time point for the largest time-matched mean difference from placebo in the QTcI interval. In females administered mirabegron at the 50 mg dose, the mean difference from placebo on QTcI interval at 5 hours post dose was 3.67 msec (upper bound of the one-sided 95% CI 5.72 msec). In males, the difference was 2.89 msec (upper bound of the one-sided 95% CI 4.90 msec). At a mirabegron dose of 200 mg, the QTcI interval did not exceed 10 msec at any time point in males, while in females the upper bound of the one-sided 95% confidence interval did exceed 10 msec between 0.5–6 hours, with a maximum difference from placebo at 5 hours where the mean effect was 10.42 msec (upper bound of the one-sided 95% CI 13.44 msec). Results for QTcF and QTcIf were consistent with QTcI.
In this TQT study, mirabegron increased heart rate on ECG in a dose dependent manner across the 50 mg to 200 mg dose range examined. The maximum mean difference from placebo in heart rate ranged from 6.7 bpm with mirabegron 50 mg up to 17.3 bpm with mirabegron 200 mg in healthy subjects.
In OAB patients (mean age of 59 years) across three 12-week phase 3 double blind, placebo-controlled studies receiving Betmiga 50 mg once daily, an increase in mean difference from placebo of approximately 1 bpm for pulse rate and approximately 1 mm Hg or less in systolic blood pressure/diastolic blood pressure (SBP/DBP) was observed. Changes in pulse rate and blood pressure are reversible upon discontinuation of treatment.
Mirabegron can increase blood pressure in paediatric patients. Blood pressure increases may be larger in children (3 to less than 12 years of age) than in adolescents (12 to less than 18 years of age). Blood pressure should be measured at baseline and periodically during treatment with mirabegron.
Mirabegron 100 mg once daily did not increase IOP in healthy adult subjects after 56 days of treatment. In a phase 1 study assessing the effect of Betmiga on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of mirabegron 100 mg was non-inferior to placebo for the primary endpoint of the treatment difference in mean change from baseline to day 56 in subject-average IOP; the upper bound of the two-sided 95% CI of the treatment difference between mirabegron 100 mg and placebo was 0.3 mm Hg.
Efficacy of mirabegron was evaluated in three phase 3 randomised, double blind, placebo-controlled, 12-week studies for the treatment of overactive bladder with symptoms of urgency and frequency with or without incontinence. Female (72%) and male (28%) patients with a mean age of 59 years (range 18–95 years) were included. The study population consisted of approximately 48% antimuscarinic treatment naïve patients as well as approximately 52% patients previously treated with antimuscarinic medicinal products. In one study, 495 patients received an active control (tolterodine prolonged release formulation).
The co-primary efficacy endpoints were (1) change from baseline to end of treatment in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment in mean number of micturitions per 24 hours based on a 3-day micturition diary. Mirabegron demonstrated statistically significant larger improvements compared to placebo for both co-primary endpoints as well as secondary endpoints (see Tables 3 and 4).
Table 3. Co-primary and selected secondary efficacy endpoints at end of treatment for pooled studies in adults:
| Parameter | Pooled studies (046, 047, 074) | |
|---|---|---|
| Placebo | Mirabegron 50 mg | |
| Mean number of incontinence episodes per 24 hours (FAS-I) (Co-primary) | ||
| n | 878 | 862 |
| Mean baseline | 2.73 | 2.71 |
| Mean change from baseline* | -1.10 | -1.49 |
| Mean difference from placebo* (95% CI) | -- | -0.40 (-0.58, -0.21) |
| p-value | -- | <0.001‡ |
| Mean number of micturitions per 24 hours (FAS) (Co-primary) | ||
| n | 1 328 | 1 324 |
| Mean baseline | 11.58 | 11.70 |
| Mean change from baseline* | -1.20 | -1.75 |
| Mean difference from placebo* (95% CI) | -- | -0.55 (-0.75, -0.36) |
| p-value | -- | <0.001‡ |
| Mean volume voided (ml) per micturition (FAS) (Secondary) | ||
| n | 1 328 | 1 322 |
| Mean baseline | 159.2 | 159.0 |
| Mean change from baseline* | 9.4 | 21.4 |
| Mean difference from placebo* (95% CI) | -- | 11.9 (8.3, 15.5) |
| p-value | -- | <0.001‡ |
| Mean level of urgency (FAS) (Secondary) | ||
| n | 1 325 | 1 323 |
| Mean baseline | 2.39 | 2.42 |
| Mean change from baseline* | -0.15 | -0.26 |
| Mean difference from placebo* (95% CI) | -- | -0.11 (-0.16, -0.07) |
| p-value | -- | <0.001‡ |
| Mean number of urgency incontinence episodes per 24 hours (FAS-I) (Secondary) | ||
| n | 858 | 834 |
| Mean baseline | 2.42 | 2.42 |
| Mean change from baseline* | -0.98 | -1.38 |
| Mean difference from placebo* (95% CI) | -- | -0.40 (-0.57, -0.23) |
| p-value | -- | <0.001‡ |
| Mean number of episodes with urgency grades 3 or 4 per 24 hours (FAS) (Secondary) | ||
| n | 1 324 | 1 320 |
| Mean baseline | 5.61 | 5.80 |
| Mean change from baseline* | -1.29 | -1.93 |
| Mean difference from placebo* (95% CI) | -- | -0.64 (-0.89, -0.39) |
| p-value | -- | <0.001‡ |
| Treatment satisfaction – visual analogue scale (FAS) (Secondary) | ||
| n | 1 195 | 1 189 |
| Mean baseline | 4.87 | 4.82 |
| Mean change from baseline* | 1.25 | 2.01 |
| Mean difference from placebo* (95% CI) | -- | 0.76 (0.52, 1.01) |
| p-value | -- | <0.001† |
Pooled studies consisted of studies 046 (Europe/Australia), 047 (North America [NA]) and 074 (Europe/NA).
* Least squares mean adjusted for baseline, gender, and study.
† Statistically significantly superior compared to placebo at the 0.05 level without multiplicity adjustment.
‡ Statistically significantly superior compared to placebo at the 0.05 level with multiplicity adjustment.
FAS: Full analysis set, all randomised patients who took at least 1 dose of double blind study drug and who had a micturition measurement in the baseline diary and at least 1 post-baseline visit diary with a micturition measurement.
FAS-I: Subset of FAS who also had at least 1 incontinence episode in the baseline diary.
CI: Confidence Interval
Table 4. Co-primary and selected secondary efficacy endpoints at end of treatment for studies 046, 047 and 074 in adults:
| Parameter | Study 046 | Study 047 | Study 074 | ||||
|---|---|---|---|---|---|---|---|
| Placebo | Mirabegron 50 mg | Tolterodine ER 4 mg | Placebo | Mirabegron 50 mg | Placebo | Mirabegron 50 mg | |
| Mean number of incontinence episodes per 24 hours (FAS-I) (Co-primary) | |||||||
| n | 291 | 293 | 300 | 325 | 312 | 262 | 257 |
| Mean baseline | 2.67 | 2.83 | 2.63 | 3.03 | 2.77 | 2.43 | 2.51 |
| Mean change from baseline* | -1.17 | -1.57 | -1.27 | -1.13 | -1.47 | -0.96 | -1.38 |
| Mean difference from placebo* | -- | -0.41 | -0.10 | -- | -0.34 | -- | -0.42 |
| 95% Confidence Interval | -- | (-0.72, -0.09) | (-0.42, 0.21) | -- | (-0.66, -0.03) | -- | (-0.76, -0.08) |
| p-value | -- | 0.003‡ | 0.11 | -- | 0.026‡ | -- | 0.001‡ |
| Mean number of micturitions per 24 hours (FAS) (Co-primary) | |||||||
| n | 480 | 473 | 475 | 433 | 425 | 415 | 426 |
| Mean baseline | 11.71 | 11.65 | 11.55 | 11.51 | 11.80 | 11.48 | 11.66 |
| Mean change from baseline* | -1.34 | -1.93 | -1.59 | -1.05 | -1.66 | -1.18 | -1.60 |
| Mean difference from placebo* | -- | -0.60 | -0.25 | -- | -0.61 | -- | -0.42 |
| 95% Confidence Interval | -- | (-0.90, -0.29) | (-0.55, 0.06) | -- | (-0.98, -0.24) | -- | (-0.76, -0.08) |
| p-value | -- | <0.001‡ | 0.11 | -- | 0.001‡ | -- | 0.015‡ |
| Mean volume voided (ml) per micturition (FAS) (Secondary) | |||||||
| n | 480 | 472 | 475 | 433 | 424 | 415 | 426 |
| Mean baseline | 156.7 | 161.1 | 158.6 | 157.5 | 156.3 | 164.0 | 159.3 |
| Mean change from baseline* | 12.3 | 24.2 | 25.0 | 7.0 | 18.2 | 8.3 | 20.7 |
| Mean difference from placebo* | -- | 11.9 | 12.6 | -- | 11.1 | -- | 12.4 |
| 95% Confidence Interval | -- | (6.3, 17.4) | (7.1, 18.2) | -- | (4.4, 17.9) | -- | (6.3, 18.6) |
| p-value | -- | <0.001‡ | <0.001† | -- | 0.001‡ | -- | <0.001‡ |
| Mean level of urgency (FAS) (Secondary) | |||||||
| n | 480 | 472 | 473 | 432 | 425 | 413 | 426 |
| Mean baseline | 2.37 | 2.40 | 2.41 | 2.45 | 2.45 | 2.36 | 2.41 |
| Mean change from baseline* | -0.22 | -0.31 | -0.29 | -0.08 | -0.19 | -0.15 | -0.29 |
| Mean difference from placebo* | -- | -0.09 | -0.07 | -- | -0.11 | -- | -0.14 |
| 95% Confidence Interval | -- | (-0.17, -0.02) | (-0.15, 0.01) | -- | (-0.18, -0.04) | -- | (-0.22, -0.06) |
| p-value | -- | 0.018† | 0.085 | -- | 0.004† | -- | <0.001§ |
| Mean number of urgency incontinence episodes per 24 hours (FAS-I) (Secondary) | |||||||
| n | 283 | 286 | 289 | 319 | 297 | 256 | 251 |
| Mean baseline | 2.43 | 2.52 | 2.37 | 2.56 | 2.42 | 2.24 | 2.33 |
| Mean change from baseline* | -1.11 | -1.46 | -1.18 | -0.89 | -1.32 | -0.95 | -1.33 |
| Mean difference from placebo* | -- | -0.35 | -0.07 | -- | -0.43 | -- | -0.39 |
| 95% Confidence Interval | -- | (-0.65, -0.05) | (-0.38, 0.23) | -- | (-0.72, -0.15) | -- | (-0.69, -0.08) |
| p-value | -- | 0.003† | 0.26 | -- | 0.005† | -- | 0.002§ |
| Mean number of episodes with urgency grades 3 or 4 per 24 hours (FAS) (Secondary) | |||||||
| n | 479 | 470 | 472 | 432 | 424 | 413 | 426 |
| Mean baseline | 5.78 | 5.72 | 5.79 | 5.61 | 5.90 | 5.42 | 5.80 |
| Mean change from baseline* | -1.65 | -2.25 | -2.07 | -0.82 | -1.57 | -1.35 | -1.94 |
| Mean difference from placebo* | -- | -0.60 | -0.42 | -- | -0.75 | -- | -0.59 |
| 95% Confidence Interval | -- | (-1.02, -0.18) | (-0.84, -0.00) | -- | (-1.20, -0.30) | -- | (-1.01, -0.16) |
| p-value | -- | 0.005† | 0.050† | -- | 0.001† | -- | 0.007§ |
| Treatment satisfaction – visual analogue scale (FAS) (Secondary) | |||||||
| n | 428 | 414 | 425 | 390 | 387 | 377 | 388 |
| Mean baseline | 4.11 | 3.95 | 3.87 | 5.5 | 5.4 | 5.13 | 5.13 |
| Mean change from baseline* | 1.89 | 2.55 | 2.44 | 0.7 | 1.5 | 1.05 | 1.88 |
| Mean difference from placebo* | -- | 0.66 | 0.55 | -- | 0.8 | -- | 0.83 |
| 95% Confidence Interval | -- | (0.25, 1.07) | (0.14, 0.95) | -- | (0.4, 1.3) | -- | (0.41, 1.25) |
| p-value | -- | 0.001† | 0.008† | -- | <0.001† | -- | <0.001† |
* Least squares mean adjusted for baseline, gender and geographical region.
† Statistically significantly superior compared with placebo at the 0.05 level without multiplicity adjustment.
‡ Statistically significantly superior compared with placebo at the 0.05 level with multiplicity adjustment.
§ Not statistically significantly superior compared to placebo at the 0.05 level with multiplicity adjustment.
FAS: Full analysis set, all randomised patients who took at least 1 dose of double blind study drug and who had a micturition measurement in the baseline diary and at least 1 post-baseline visit diary with a micturition measurement.
FAS-I: Subset of FAS who also had at least 1 incontinence episode in the baseline diary.
Betmiga 50 mg once daily was effective at the first measured time point of week 4, and efficacy was maintained throughout the 12-week treatment period. A randomised, active controlled, long term study demonstrated that efficacy was maintained throughout a 1-year treatment period.
In the three 12-week phase 3 double blind, placebo-controlled studies, treatment of the symptoms of OAB with mirabegron once daily resulted in a statistically significant improvement over placebo on the following health-related quality of life measures: treatment satisfaction and symptom bother.
Efficacy was demonstrated in patients with and without prior OAB antimuscarinic therapy. In addition, mirabegron showed efficacy in patients who previously discontinued OAB antimuscarinic therapy due to insufficient effect (see Table 5).
Table 5. Co-primary efficacy endpoints for adult patients with prior OAB antimuscarinic therapy:
Efficacy of mirabegron tablets and oral suspension was evaluated in a 52-week, open-label, baseline-controlled, multicentre, dose titration study for the treatment of NDO in paediatric patients. Patients had a diagnosis of NDO with involuntary detrusor contractions with detrusor pressure increase greater than 15 cm H2O and performed clean intermittent catheterisation (CIC). Patients ≥35 kg received tablets and patients <35 kg (or ≥35 kg but unable to tolerate tablets) received oral suspension. For all patients, mirabegron was administered orally once daily with food. The starting dose (PED25) was a 25 mg tablet or between 3-6 ml of oral suspension (depending on patient weight). This dose was up-titrated to PED50, a 50 mg tablet or between 6-11 ml of oral suspension (depending on body weight). The dose titration period was a maximum of 8 weeks followed by a dose maintenance period of at least 52 weeks.
A total of 86 patients aged 3 to less than 18 years of age received mirabegron. Of these, 71 patients completed treatment through week 24 and 70 completed 52 weeks of treatment. A total of 68 patients had valid urodynamic measurements for evaluation of efficacy. The study population included 39 (45.3%) males and 47 (54.7%) females. The optimised maintenance dose within this study population included 94% of patients at the maximum dose, and 6% of patients at the starting dose.
The most common (in greater than 10% of all patients) background medical conditions related to NDO in children and adolescents included in the study were congenital central nervous system anomaly (54.5% and 48.4%, respectively), meningomyelocele (27.3% and 19.4%, respectively), and spina bifida (10.9% and 12.9%, respectively). In adolescents, 12.9% had a spinal cord injury.
The primary efficacy endpoint was change from baseline in maximum cystometric capacity (MCC) after 24 weeks of mirabegron treatment. Improvements in MCC were observed in all patient groups (see Table 6).
Table 6. Primary efficacy endpoint in paediatric patients with NDO:
| Parameter | Children aged 3 to <12 years (N=43)* Mean (SD) | Adolescents aged 12 to <18 years (N=25)* Mean (SD) |
|---|---|---|
| Maximum cystometric capacity (ml) | ||
| Baseline Week 24 Change from baseline 95% Confidence Interval | 158.6 (94.5) 230.7 (129.1) 72.0 (87.0) (45.2, 98.8) | 238.9 (99.1) 352.1 (125.2) 113.2 (82.9) (78.9, 147.4) |
* N is the number of patients who took at least one dose and provided valid values for MCC at baseline and week 24.
The secondary efficacy endpoints were change from baseline in bladder compliance, number of overactive detrusor contractions, detrusor pressure at end of bladder-filling, bladder volume prior to first detrusor contraction, maximum catheterised urine volume per day, and number of leakage episodes per day after 24 weeks of mirabegron treatment (see Table 7).
Table 7. Secondary efficacy endpoints in paediatric patients with NDO:
| Parameter | Children aged 3 to <12 years (N=43)* Mean (SD) | Adolescents aged 12 to <18 years (N=25)* Mean (SD) |
|---|---|---|
| Bladder compliance (ml/cm H2O)† | ||
| Baseline Week 24 Change from baseline 95% Confidence Interval | 14.5 (50.7) 29.6 (52.8) 14.6 (42.0) (-0.3, 29.5) | 11.0 (10.0) 23.8 (15.3) 13.5 (15.0) (6.7, 20.4) |
| Number of overactive detrusor contractions (>15 cm H2O)† | ||
| Baseline Week 24 Change from baseline 95% Confidence Interval | 3.0 (3.8) 1.0 (2.2) -1.8 (4.1) (-3.2, -0.4) | 2.0 (2.9) 1.4 (2.3) -0.7 (3.8) (-2.4, 0.9) |
| Detrusor pressure (cm H2O) at end of bladder-filling† | ||
| Baseline Week 24 Change from baseline 95% Confidence Interval | 42.2 (26.2) 25.6 (21.2) -18.1 (19.9) (-24.8, -11.3) | 38.6 (17.9) 27.8 (27.8) -13.1 (19.9) (-22.0, -4.3) |
| Bladder volume prior to first detrusor contraction (>15 cm H2O)† | ||
| Baseline Week 24 Change from baseline 95% Confidence Interval | 115.8 (87.0) 207.9 (97.8) 93.1 (88.1) (64.1, 122.1) | 185.2 (121.2) 298.7 (144.4) 121.3 (159.8) (53.8, 188.8) |
| Maximum catheterised urine volume per day (ml)† | ||
| Baseline Week 24 Change from baseline 95% Confidence Interval | 300.1 (105.7) 345.9 (84.6) 44.2 (98.3) (13.2, 75.2) | 367.5 (119.0) 449.9 (146.6) 81.3 (117.7) (30.4, 132.3) |
| Number of leakage episodes per day† | ||
| Baseline Week 24 Change from baseline 95% Confidence Interval | 3.2 (3.7) 0.7 (1.2) -2.0 (3.2) (-3.2, -0.7) | 1.8 (1.7) 0.9 (1.2) -1.0 (1.1) (-1.5, -0.5) |
* N is the number of patients who took at least one dose and provided valid values for MCC at baseline and week 24.
† Number of patients (children/adolescents) with data available for both baseline and week 24; Bladder compliance: n=33/21; Number of overactive detrusor contractions: n=36/22; Detrusor pressure at end of bladder-filling: n=36/22; Bladder volume prior to first detrusor contraction: n=38/24; Maximum catheterised urine volume per day: n=41/23; Number of leakage episodes per day: n=26/21.
Patient- or clinician-reported questionnaire endpoints included acceptability, change from baseline in the Pediatric Incontinence Questionnaire (PIN-Q), change from baseline in the Patient Global Impression of Severity Scale (PGI-S), and Clinician Global Impression of Change (CGI-C) (see Table 8).
Table 8. Patient- or clinician-reported questionnaire endpoints in paediatric patients with NDO:
| Parameter | Children aged 3 to <12 years (N=43)* Mean (SD) | Adolescents aged 12 to <18 years (N=25)* Mean (SD) |
|---|---|---|
| Pediatric Incontinence Questionnaire (PIN-Q) score† | ||
| Baseline Week 24 Change from baseline 95% Confidence Interval | 30.8 (15.7) 30.6 (15.2) 2.0 (10.5) (-2.4, 6.4) | 29.4 (14.6) 25.2 (15.5) -4.9 (14.1) (-11.3, 1.5) |
| Total Patient Global Impression of Severity Scale (PGI-S) score† | ||
| Baseline Week 24 Change from baseline 95% Confidence Interval | 2.2 (0.8) 2.6 (0.8) 0.3 (1.2) (-0.1, 0.8) | 2.3 (0.9) 3.0 (0.7) 0.6 (1.0) (0.1, 1.0) |
| Total Clinician Global Impression of Change (CGI-C) at week 24, N (%)† | ||
| Very Much Improved Much Improved Minimally Improved No Change Minimally Worse Much Worse Very Much Worse | 6 (14.6%) 24 (58.5%) 6 (14.6%) 4 (9.8%) 1 (2.4%) 0 0 | 10 (41.7%) 7 (29.2%) 5 (20.8%) 1 (4.2%) 1 (4.2%) 0 0 |
* N is the number of patients who took at least one dose and provided valid values for MCC at baseline and week 24.
† Number of patients (children/adolescents) with data available for both baseline and week 24. PIN-Q score: n=24/21, Total PGI-S score: n=25/22; Total CGI-C at week 24: n=41/24.
The European Medicines Agency has waived the obligation to submit the results of studies with Betmiga in all subsets of the paediatric population in “Treatment of idiopathic overactive bladder” (see section 4.2 for information on paediatric use).
After oral administration of mirabegron in healthy volunteers mirabegron is absorbed to reach peak plasma concentrations (Cmax) between 3 and 4 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 over the dose range. In the overall adult 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 mg to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady-state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady-state is approximately double that seen after a single dose.
The median Tmax of mirabegron following oral administration of a single dose of mirabegron tablets or oral suspension in patients under fed state was 4-5 hours. Population pharmacokinetic analysis predicted that the median Tmax of mirabegron tablets or oral suspension at steady-state was 3-4 hours.
The bioavailability of the oral suspension formulation is lower than that of the tablet. The ratio of the population mean exposure (AUCtau) of the oral suspension to the tablet is approximately 45%.
Co-administration of a 50 mg tablet with a high-fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In the phase 3 studies, mirabegron was administered with or without food and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose.
The population pharmacokinetic model predicted that the patients receiving mirabegron in the fed state would have 44.7% of steady-state AUCtau relative to an equal dose administered in the fasted state. This value is consistent with the AUCinf results seen in the single-dose food effects studies for mirabegron. In the phase 3 paediatric study, mirabegron was administered with food and demonstrated both safety and efficacy. Dosing recommendations are based upon the exposures expected in the fed state. Therefore, in paediatric patients, mirabegron should be taken with food at the recommended dose.
Mirabegron is extensively distributed. The volume of distribution at steady-state (Vss) is approximately 1 670 l. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. In vitro erythrocyte concentrations of 14C-mirabegron were about 2-fold higher than in plasma.
Mirabegron volume of distribution was relatively large and increased with increasing body weight in accordance with allometric principles based on population pharmacokinetic analysis. Age, sex and patient population had no impact on volume of distribution after accounting for potential differences in body weight.
Mirabegron is metabolised 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 adult human plasma; both are phase 2 glucuronides representing 16% and 11% of total exposure. These metabolites are not pharmacologically active.
Based on in vitro studies, mirabegron is unlikely to inhibit the metabolism of co-administered medicinal products metabolised 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 is predicted not to cause clinically relevant inhibition of OCT-mediated drug transport.
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 vitro and ex vivo studies have shown the involvement from butyrylcholinesterase, UGT and possibly alcohol dehydrogenase (ADH) in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6.
In healthy adult subjects who are genotypically poor metabolisers of CYP2D6 substrates (used as a surrogate for CYP2D6 inhibition), mean Cmax and AUCinf of a single 160 mg dose of a mirabegron IR formulation were 14% and 19% higher than in extensive metabolisers, indicating that CYP2D6 genetic polymorphism has minimal impact on the mean plasma exposure to mirabegron. Interaction of mirabegron with a known CYP2D6 inhibitor is not expected and was not studied. No dose adjustment is needed for mirabegron when administered with CYP2D6 inhibitors or in adult patients who are CYP2D6 poor metabolisers.
Total body clearance (CLtot) from plasma is approximately 57 l/h. The terminal elimination half-life (t1/2) is approximately 50 hours. Renal clearance (CLR) is approximately 13 l/h, which corresponds to nearly 25% of CLtot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary excretion 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 to healthy volunteers, approximately 55% of the radiolabel was recovered in the urine and 34% in the faeces. Unchanged mirabegron accounted for 45% of the urinary radioactivity, indicating the presence of metabolites. Unchanged mirabegron accounted for the majority of the faecal radioactivity.
Mirabegron clearance was predicted to increase in patients with increasing body weight in accordance with allometric principles based on population pharmacokinetic analysis. The apparent clearance parameter was impacted significantly by dose, formulation, and food effects on relative bioavailability. Values of apparent clearance were highly variable but generally similar between children and adolescents, despite body weight differences, because of these effects on bioavailability.
The Cmax and AUC of mirabegron and its metabolites following multiple oral doses in elderly volunteers (≥65 years) were similar to those in younger volunteers (18–45 years).
In patients 3 to less than 18 years of age, age was not predicted to have any impact on key mirabegron pharmacokinetic parameters after accounting for differences in body weight. Models including age did not result in meaningful improvements to the paediatric population pharmacokinetic model, indicating that inclusion of body weight was sufficient to address differences in mirabegron pharmacokinetics due to age.
The Cmax and AUC of mirabegron and its metabolites following multiple oral doses in elderly volunteers (≥65 years) were similar to those in younger volunteers (18–45 years).
In patients 3 to less than 18 years of age, age was not predicted to have any impact on key mirabegron pharmacokinetic parameters after accounting for differences in body weight. Models including age did not result in meaningful improvements to the paediatric population pharmacokinetic model, indicating that inclusion of body weight was sufficient to address differences in mirabegron pharmacokinetics due to age.
The Cmax and AUC are approximately 40% to 50% higher in females than in males. Gender differences in Cmax and AUC are attributed to differences in body weight and bioavailability.
Gender has no meaningful impact on mirabegron pharmacokinetics in the paediatric population from 3 to less than 18 years of age.
The pharmacokinetics of mirabegron in adults are not influenced by race.
Following single dose administration of 100 mg Betmiga in adult volunteers with mild renal impairment (eGFR-MDRD 60 to 89 ml/min/1.73 m²), mean mirabegron Cmax and AUC were increased by 6% and 31% relative to adult volunteers with normal renal function. In adult volunteers with moderate renal impairment (eGFR-MDRD 30 to 59 ml/min/1.73 m²), Cmax and AUC were increased by 23% and 66%, respectively. In adult volunteers with severe renal impairment (eGFR-MDRD 15 to 29 ml/min/1.73 m²), mean Cmax and AUC values were 92% and 118% higher. Mirabegron has not been studied in patients with ESRD (eGFR <15 ml/min/1.73 m²) or patients requiring haemodialysis.
Following single dose administration of 100 mg Betmiga in adult volunteers with mild hepatic impairment (Child-Pugh Class A), mean mirabegron Cmax and 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 Cmax and AUC values were 175% and 65% higher. Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
Pre-clinical studies have identified target organs of toxicity that are consistent with clinical observations. Transient increases in liver enzymes and hepatocyte changes (necrosis and decrease in glycogen particles) were seen in rats and reduced plasma leptin levels were noted. An increase in heart rate was observed in rats, rabbits, dogs and monkeys. Genotoxicity and carcinogenicity studies have shown no genotoxic or carcinogenic potential in vivo.
Mirabegron had no discernible effect on gonadotropic or sex steroid hormone levels. In addition, no effects on fertility were seen at sub-lethal doses (human equivalent dose was 19-fold higher than the maximum human recommended dose (MHRD)). The main findings in rabbit embryofetal development studies included malformations of the heart (dilated aorta, cardiomegaly) at systemic exposures 36-fold higher than observed at the MHRD. In addition, malformations of the lung (absent accessory lobe of the lung) and increased post-implantation loss were observed in the rabbit at systemic exposures 14-fold higher than observed at the MHRD, while in the rat reversible effects on ossification were noted (wavy ribs, delayed ossification, decreased number of ossified sternebrae, metacarpi or metatarsi) at systemic exposures 22-fold higher than observed at the MHRD. The observed embryofetal toxicity occurred at doses associated with maternal toxicity. The cardiovascular malformations observed in the rabbit were shown to be mediated via activation of the beta 1-adrenoceptor.
The overall safety profile seen in juvenile rats was comparable to that observed in adult animals. Repeat dose safety studies performed in juvenile rats showed no effect on physical development or sexual maturation. Mirabegron administration from weaning through sexual maturation had no effect on mating ability, fertility or embryofoetal development. Mirabegron administration increased lipolysis and food consumption in juvenile rats.
Pharmacokinetic studies performed with radio-labelled mirabegron have shown that the parent compound and/or its metabolites are excreted in the milk of rats at levels that were approximately 1.7-fold higher than plasma levels at 4 hours post administration (see section 4.6).
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