Pharmacodynamics

Mechanism of Action

Contraction of the urinary bladder is known to be induced by acetylcholine with mediation of muscarinic acetylcholine receptor subtype M3. Acetylcholine release from the nerve terminal of the urinary bladder is probably enhanced by a stimulus to muscarinic acetylcholine receptor subtype M1. lmidafenacin antagonizes subtypes M3 on the smooth muscle of the bladder and M1 in vitro. In the urinary bladder, imidafenacin inhibits acetylcholine release by antagonizing subtype M1 and contraction of smooth muscles by antagonizing subtype M3. Compared with the inhibitory effect on the salivary gland, imidafenacin shows higher inhibitory effect on the urinary bladder contraction, probably indicating efficacy and safety of this product in clinical practice.

Activity in the muscarinic acetylcholine receptor subtypes (In vitro)

  1. Antagonistic activity of imidafenacin was investigated on muscarinic acetylcholine receptors in vas deferens (M1), atrium (M2), and ileum (M3) using tissue specimens prepared from rabbits and guinea pigs. Imidafenacin showed higher antagonistic activity in the ileum (M3) and vas deferens (M1), compared with the atrium (M2). Major metabolites in humans showed no antagonistic activity in the muscarinic acetylcholine receptor subtypes.
  2. Antagonistic activity of imidafenacin was investigated in recombinant human muscarinic acetylcholine receptor subtypes M1, M2, and M3 in the receptor binding assay. lmidafenacin showed high affinities for subtypes M3 and M1.
  3. lmidafenacin inhibited acetylcholine release and urinary bladder contraction by antagonizing subtypes M3 and M1 in the tissue specimens prepared from rats.

Activity In the urinary bladder (In vivo)

  1. lmidafenacin decreased rhythmic contraction of the rat urinary bladder dose-dependently.
  2. lmidafenacin inhibited a carbachol-induced decrease in the capacity of the rat urinary bladder dose dependently.

Selectivity for the urinary bladder

  1. In rats, the activity ratio of inhibition of rhythmic contraction in the urinary bladder to carbachol-induced salivary secretion was about 10 times higher in imidafenacin than in propiverine hydrochloride, demonstrating high selectivity of imidafenacin for the urinary bladder.
  2. Evaluation of rat performance in the Morris water maze task indicated that antagonistic activity of imidafenacin on subtype M1 was unlikely to impair spatial learning and memory.

Clinical Studies

  1. Double-blind Placebo-controlled Study:

lmidafenacin was orally administered at the dose of 0.1 mg twice daily for 12 weeks to patients with overactive bladder. For the primary efficacy outcome, change in total number of urinary incontinence per week from the baseline value, significant improvement was observed in the imidafenacin group compared with the placebo group. In addition, significant improvement was also observed in changes in mean frequency of urination per day and mean frequency of urinary urgency per day from the baseline values in the imidafenacin group compared with the placebo group.

Adverse reactions in the imidafenacin group including abnormalities in laboratory test values were reported in 130 (40.5%) of 321 cases evaluated. Major adverse reactions included thirst in 87 cases (27.1%) and constipation in 30 cases (9.3%).

Outcome Group At baseline (Note) After 4 weeks After 12 weeks or at discontinuation
Total number of urinary incontinence per week (change in %) Placebo 17.55±11.18 -33.50±51.34 -49.50±57.22
Imidafenacin 18.56±14.81 -48.67 ±44.75## -68.24 ±36.90###
Mean frequency of urination per day (change in number) Placebo 11.47±2.50 -1.04±1.74 -1.08±1.62
Imidafenacin 11.20±2.28 -1.19 ±1.58 -1.52 ± 1.70#
Mean frequency of urinary urgency per day (change in %) Placebo 5.42±3.57 -20.83 ±46.24 -35.63±53.71
Imidafenacin 4.87±2.90 -34.58 ±43.83## -53.39 ±41.35###
Note: Abstracted from the results of the Phase Ill comparative clinical study conducted to verify superiority of imidafenacin to placebo and non-inferiority of imidafenacin to propiverine hydrochloride.
Placebo group: 143 cases, imidafenacin group: 318 cases
Mean ± S.D., #: p<0.05, ##: p<0.01 , ###: p<0.001 (vs. placebo group)
Note) Measurement values are presented for the baselinevalues.

 

2. Long-term Study

lmidafenacin was orally administered at the dose of 0.1 mg twice daily for 52 weeks to patients with overactive bladder. Improvement was observed in changes in total number of urinary incontinence per week, mean frequency of urination per day, and mean frequency of urinary urgency per day from the baseline values, with duration for 52 weeks without attenuation. Adverse reactions in the imidafenacin group including abnormalities in laboratory test values were reported in 223 (46.7%) of 478 cases evaluated. Major adverse reactions included thirst in 164 cases (34.3 %) and constipation in 43 cases (9.0%).

Outcome At baseline (Note) After 12 weeks After 28 weeks After 52 weeks or at discontinuation
Cases 364 355 355 363
Total number of urinary incontinence per week (change in %) 14.53 ± 14.47 -55.92 ± 75.52# -70.83 ± 50.56# -83.51 ± 35.48#
Mean frequency of urination per day (change in number) 11.56 ± 2.81 -1.65 ± 2.12# -2.05 ± 2.26# -2.35 ± 2.14#
Mean frequency of urinary urgency per day (change in %) 4.84 ± 3.18 -45.81 ± 53.37# -55.67 ± 48.65# -70.53 ± 38.37#
Mean ± S.D., #: p<0.05, (vs. baseline values)
Note) Measurement values are presented for the baseline values.

 

3. Long-term Ascending-dose Study

lmidafenacin was orally administered at the dose of 0.1 mg twice daily for 12 weeks to patients with overactive bladder. Then, imidafenacin was orally administered at the dose of 0.2 mg twice daily for 52 weeks in the dose increased group, and at the dose of 0.1 mg twice daily for 40 weeks in the dose maintained group according to the criteria for dose increase. In the group of 0.4 mg/day, improvement was observed in changes in total number of urinary incontinence per week, mean frequency of urination per day, and mean frequency of urinary urgency per day from the baseline values, with duration for 64 weeks after the start of the study (52 weeks after dose increase) without attenuation.

There were 49.4% (215 of 435) patients who experienced adverse drug reactions including abnormalities in laboratory test values, reported in the safety analysis set. Among them, 62.6% (114 of 182) of patients were in the dose increased group and 39.9% (101 of 253) of patients were in the dose maintained group. The most common adverse drug reactions were dry mouth and constipation, and the incident ratios were 53.3% (97 of 182) and 18. 7% (34 of 182) in the dose increased group, 26.5% (67 of 253) and 9.9% (25 of 253) in the dose maintained group, respectively.

Outcome Long-term ascending-dose study at 0.4 mg/day (dose increased cases) At baseline Note) After 12 weeks After 24 weeks (12 weeks after dose increase) After 64 weeks (52 weeks after dose increase) or at discontinuation
Cases 159 159 158 159
Total number of episodes of urinary incontinence per week (change in %) 14.01 ± 13.29 -22.92 ± 75.22### -69.97 ± 42.93### -79.30 ± 41.01###
Mean frequency of urination per day (change in number) 11.86 ± 2.44 -0.82 ± 1.70### -2.03 ± 2.01### -2.11 ± 2.06###
Mean frequency of urinary urgency per day (change in %) 4.96 ± 2.99 -23.67 ± 43.29### -58.58 ± 40.25### -65.62 ± 38.69###
Mean± SD;###, p-<0.001 (vs. baseline values)
Note) Measurement values are presented for baseline values.
Note: Criteria for dose increase: If all symptoms of overactive bladder failed to meet the normalization criteria (mean frequency of urinary urgency per day of 0 [disappearance], (mean frequency of urination per day of less than eight, and total number of episodes of urinary incontinence per week of 0 [disappearance]) at the visit after administration of the initial dose for 12 weeks, the dose of imidafenacin may be increased when the investigator judged that the dose increase should be valid, and the patient requested the dose increase. If, however, moderate to severe adverse reaction(s) had developed before the visit after 12 weeks of administration, dose increase should not be conducted.