Ther Adv Urol (2013) 5(1) 43 –58 DOI: 10.1177/
1756287212459549
© The Author(s), 2012.
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Therapeutic Advances in Urology Review
Introduction
Overactive bladder (OAB) is a chronic syndrome defined by symptoms of urinary urgency with no underlying medical causes [Abrams et al. 2002].
The most prevalent symptom is urinary urgency which is generally accompanied by urinary fre- quency and nocturia, or urgency incontinence [Abrams et al. 2002]. OAB is a common disease with an overall prevalence of at least 16% in adults in the USA and Europe [Milsom et al. 2001;
Stewart et al. 2003]. In Japan, the incidence of OAB in men and women aged at least 40 years is 12.4% [Homma et al. 2005]. Furthermore, OAB is strongly correlated with age; for example, the incidence of OAB in older people (≥70 years old) in Japan exceeds 30% [Homma et al. 2005]. OAB is associated with a reduced quality of life and influences the social, psychological, occupational, daily living, physical and sexual aspects of a patient’s life [Abrams et al. 2000].
First-line treatment of OAB comprises fluid intake advice and bladder training, supplemented
by anticholinergic drugs if necessary. As OAB is a chronic disease, anticholinergics should be chosen based on long-term efficacy and safety.
There are a variety of anticholinergic drugs avail- able in Japan for the treatment of OAB: solifena- cin succinate, tolterodine tartrate, propiverine, oxybutynin chloride and imidafenacin (Table 1).
While these all act on muscarinic receptors, they have different tolerability profiles. Those which are not specific for the bladder cause adverse effects such as dry mouth, constipation, blurred vision or cognitive impairment [Andersson, 2004].
In comparison, imidafenacin (a newer anticho- linergic which has been marketed in Japan since 2007) was developed to improve the tolerability of anticholinergic therapy by being specific for the M3 receptor subtype which is found mainly in the bladder [Andersson, 2004]. This article provides an overview of the pharmacokinetics, pharmacological properties, clinical efficacy and tolerability of imidafenacin in the treatment of OAB, including our experience in the LIST study.
Experience with imidafenacin in the
management of overactive bladder disorder
Takumi Takeuchi, Masayoshi Zaitsu and Koji Mikami
Abstract: Overactive bladder (OAB) is a chronic syndrome defined by symptoms of urinary urgency with no underlying medical causes. First-line treatment of OAB comprises fluid intake advice and bladder training, supplemented by anticholinergic drugs if necessary. Owing to the chronic nature of OAB, the ideal anticholinergic treatment should have good long-term efficacy and tolerability. There are many anticholinergics available, although some of these are not specific for the bladder and can cause adverse effects such as dry mouth, constipation, blurred vision or cognitive impairment. Imidafenacin (a newer anticholinergic which has been marketed in Japan since 2007) was developed to improve the tolerability of anticholinergic therapy. This article summarizes the pharmacological properties, pharmacokinetics, clinical efficacy and tolerability of imidafenacin in the treatment of OAB. Data from key clinical studies of imidafenacin show that it has a fast onset of action and is effective for the treatment of OAB.
It selectively binds to muscarinic receptors in the bladder and is associated with a good safety profile compared with other anticholinergics. The clinical efficacy, superior tolerability and adjustable dosing of imidafenacin make it a good anticholinergic for the treatment of OAB.
Keywords: bladder selectivity, efficacy, imidafenacin, overactive bladder, pharmacokinetics, tolerability
Correspondence to:
Takumi Takeuchi, MD, PhD
Department of Urology, Kanto Rosai Hospital, 1-1 Kizukisumiyoshi-cho, Nakahara-ku, Kawasaki 211-8510, Japan [email protected].
ne.jp
Masayoshi Zaitsu, MD, Koji Mikami, MD Department of Urology, Kanto Rosai Hospital, Kawasaki, Japan
Table 1. Anticholinergic drugs available in the Japanese market for the treatment of overactive bladder.
Drug Imidafenacin Solifenacin
succinate Tolterodine
tartrate Propiverine Oxybutynin
chloride
Approval date in Japan 2007 2006 2006 1993 1988
Dosage and administration
Formulation Tablet Tablet Capsule Tablet Tablet
Orally
disintegrating Orally
disintegrating Granule
Recommended dosing 0.1 mg twice
a day 5 mg once a
day 4 mg once a
day 20 mg once a
day 2–3 mg three
times a day 0.2 mg twice
a day 10 mg once a
day 20 mg twice a
day
Dose adjustments None Hepatic
impairment Hepatic
impairment None None
Renal
impairment Renal impairment Pharmacokinetics
Half-life (h) 2.9 38 11.3 14.8 0.9
Elimination in urine (%) 65.6 69.2 77 16 22.2
% of unaltered drug
eliminated in urine 9.4 14.7 <1 – –
Pharmacodynamics
Metabolic enzyme CYP3A4/
UGT1A2 CYP3A4/
CYP2C19 CYP3A4/
CYP2D6 CYP3A4 –
Pharmacological activity
of the metabolite None Yes Yes Yes Yes
Anticholinergic effect M3≥M1>M2 M3>M1>M2 No selectivity No selectivity (calcium antagonistic effect)
No selectivity (smooth muscle relaxant) Muscarinic selectivity [Kobayashi et al. 2007b; Ohtake et al. 2008; Yamazaki et al. 2011]
Efficacy ratio of
salivary:bladder binding X8.8 – X5.0 X0.9 X1.9
– X6.5 X2.4 X1.1 –
X15 X1.7 X2.5 X1.1 –
Receptor binding duration (h)
Citation Yamada et al.
[2011b] Oki et al. [2005] Oki et al.
[2006] Ito et al. [2010] Maruyama et al. [2008]
Bladder 3–6 1–6 6–12 3–6 2
Salivary glands 1–3 1–6 – 3 0.5–2
Colon – 1–12 – 3–6 0.5–6
Phase III trials
Citations Homma and
Yamaguchi [2009]
Cardozo et al.
[2006]; Chapple et al. [2006];
Staskin and Te [2006]
Homma et al.
[2003] Yoshida et al.
[2010] Koyanagi
et al. [1986]
Control arm Propiverine Propiverine Oxybutynin
chloride Placebo Placebo
Treatment period 12 weeks 12 weeks 12 weeks 2 weeks 2 weeks
Adverse events (%) 45.5 45.5 54.6 20.9 13.9
Drug Imidafenacin Solifenacin
succinate Tolterodine
tartrate Propiverine Oxybutynin
chloride Long-term (52-week) trial
Citations Homma and
Yamaguchi [2008]
Cardozo et al.
[2006]; Chapple et al. [2006];
Staskin and Te [2006]
Takei and
Homa [2005] Yoshida et al.
[2010] –
Adverse events (%) 46.7 5 mg 58.8 54.3 18.0 –
10 mg 64.6 Table 1. (Continued)
Pharmacokinetics
Details of the key phase I trials of imidafenacin are summarized in Table 2.
Imidafenacin has a short half-life and undergoes urinary excretion within 24 h of administration (with the exception of its M-4 metabolite which is excreted within 48 h) [Shimada et al. 2007d].
Plasma half-life values for single oral doses of imi- dafenacin 0.025, 0.05, 0.1, 0.25 or 0.5 mg in healthy volunteers were 2.6–3.0 h [Shimada et al.
2007d]. Although it has been suggested that a short half-life could contribute to an unaccepta- ble tolerability profile, this was not the case with imidafenacin. In this single-dose pharmacokinetic trial imidafenacin had an acceptable tolerability profile [Shimada et al. 2007d].
After repeated doses of imidafenacin there was no drug accumulation in healthy volunteers [Shimada et al. 2007b]. Oral imidafenacin 0.25 mg twice daily for 5 days had a peak plasma concentration (Cmax) and pharmacokinetic parameters compara- ble to those after the initial dose [Shimada et al.
2007b]. This lack of accumulation means that adverse events can be easily managed. In case of urinary retention, symptoms are easily reduced by stopping treatment. In contrast, urinary retention symptoms induced by other anticholinergic treat- ments with a long half-life (such as solifenacin) can persist after treatment cessation [Zaitsu et al.
2011].
The pharmacokinetics of imidafenacin are not greatly influenced by food or age. In the fed versus fasted state, the area under the plasma concentra- tion–time curve from time 0 to 12 h (AUC0–12) and Cmax increased by about 1.3 and 1.2 times, respectively [Shimada et al. 2007a]. A single oral dose of imidafenacin 0.1 mg in healthy older men
showed that the Cmax of imidafenacin was about 1.2 times higher than that in younger patients (determined in an earlier study) [Shimada et al.
2007d], while the AUC from time 0 to infinity (AUC0–∞) was similar between patient groups [Shimada et al. 2007c]. Data suggest that there is no need to adjust the imidafenacin dose in patients with lowered metabolic function; whether it is due to age, sex or metabolic enzyme genotype [Shimada et al. 2007c].
Finally, the metabolites of imidafenacin have no pharmacological activity [Kobayashi et al. 2007a].
A preclinical study showed that, while imidafena- cin has a high affinity for the muscarinic acetyl- choline receptor subtypes, its metabolites (M-2, M-4 and M-9) had low affinity for these receptor subtypes [Kobayashi et al. 2007a].
Imidafenacin selectivity
Involuntary contractions of the detrusor muscle, the smooth muscle wall of the bladder, via the action of acetylcholine at the muscarinic recep- tor (in particular at the M2 and M3 receptor subtypes) is presumed to be the main cause of OAB [Wein, 2001; Chapple et al. 2002; Andersson, 2004]. The M2 receptor is the main cholinergic receptor in the urinary bladder; however, its function is not well defined [Wein, 2001; Chapple et al. 2002; Andersson, 2004]. Conversely, the M3 receptor is known to be directly involved with detrusor muscle contraction [Wein, 2001;
Chapple et al. 2002; Andersson, 2004].
Muscarinic receptors also mediate gastrointesti- nal motility (M3), salivary gland function (M1, M3), heart rate and cardiac output (M2), cogni- tive processing (M1) and contraction of the ciliary muscle in the eye (M3) [Herbison et al.
2003; Andersson, 2004].
Table 2. Summary of the pharmacokinetics of imidafenacin.
Study Study design, patient population and characteristics (n)
Dosage of
imidafenacin Treatment
duration Pharmacokinetics Safety summary
Single dose study [Shimada et al. 2007d]
Phase I safety and PK in healthy adult male volunteers (32)
0.025 mg oral 0.05 mg oral 0.1 mg oral 0.25 mg oral 0.5 mg oral
Single dose Unchanged drug:
Cmax 109, 180, 382, 1010 and 1940 pg/ml
Tmax (median) 1.5–1.8 h t½ 2.6–3.0 h
Urinary excretion 5.5–8.6%
Time to urinary excretion <24 h M-2 metabolite:
Cmax 26, 51, 110, 293 and 445 pg/ml Tmax (median) 1.5–2.0 h
t½ 2.6–3.3 h*
Urinary excretion 5.9–7.1%
Time to urinary excretion <24 h
AEs
Ventricular
extrasystoles: short run in 1 subject (0.05 mg); single occurrence in 2 subjects (0.5 mg) Supraventricular
extrasystoles: single occurrence in 1 subject (0.5 mg) Electrocardiogram
ambulatory abnormal: single occurrence in 3 subjects (0.1 mg) Dry mouth: 1 subject
(0.25 mg), 3 subjects (0.5 mg)
Asthenopia (tired eyes): 1 subject (0.5 mg)
White blood cells urine positive: 1 subject (0.1 mg), 1 subject (0.5 mg) Repeated
dose study [Shimada et al. 2007b]
Phase I safety and PK in healthy adult male volunteers (6)
0.25 mg oral
twice a day 5 days Unchanged drug: AEs:
Single dose Day 5 Dry mouth: 1 subject Cmax 1240 pg/ml
Tmax (median) 1.0 h
t½ 2.8 h AUC0–12 5580
pg.h/ml AUC0–∞ 5970
pg.h/ml CL/F 42.3
liters/h Vd/F 202 liters
Cmax 1240 pg/
ml
Tmax (median) 2.0 h
t½ 2.7 h
Increased AST and ALT: 1 subject
M-2 metabolite:
Single dose Day 5 Cmax 175 pg/ml
Tmax (median) 3.0 h
t½ 3.5 h AUC0-12 1100
pg.h/ml AUC0–∞ 1280
pg.h/ml
Cmax 189 pg/ml Tmax (median)
4.0 h t½ 4.0 h AUC0–12 1290
pg.h/ml AUC0–∞ 1520
pg.h/ml
Study Study design, patient population and characteristics (n)
Dosage of
imidafenacin Treatment
duration Pharmacokinetics Safety summary
Food-effect study [Shimada et al. 2007a]
Phase I fasted and fed PK in healthy adult male Japanese volunteers (12)
0.1 mg oral Single dose Fasted state AEs
Unchanged drug Cmax 471 pg/ml Tmax (median)
1.5 h t½ 2.9 h AUC0–∞ 2400
pg.h/ml
Urinary recovery 7.3%
M-2 metabolite Cmax 97.9 pg/
ml
Tmax (median) 2.0 h
Urinary recovery 4.4%
Constipation:
mild constipation reported in 1 subject in the fasted state Dry mouth: mild dry
mouth reported in 1 subject in the fed state
Fed state:
Cmax 611 pg/ml
Tmax (median) no difference versus fasted state
AUC0-∞ slight increase versus fasted state
Urinary recovery 31.0%
Older subjects [Shimada et al. 2007c]
Phase I safety and PK in elderly (≥65 yrs) male and female subjects (9)
0.1 mg oral Single dose Unchanged drug: AEs
Cmax 445 pg/ml Tmax (median) 1.0 h t½ 3.1 h
Urinary excretion 4.9%
No adverse events or changes in laboratory values were reported M-2 metabolite:
Cmax 159 pg/ml Tmax (median) 2.0 h t½ 3.6 h
Urinary excretion 6.6%
*Doses of 0.1, 0.25 and 0.5 mg only
AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; AUC0–12, area under the plasma concentration-time curved from time 0 to 12 h; AUC0–∞, area under the plasma concentration-time curved from time 0 to infinity; CL/F, apparent total clearance; Cmax, peak plasma concentration; PK, pharmacokinetic; t½, half-life; Tmax, time to peak plasma concentration; Vd/F, apparent volume of distribution.
Table 2. (Continued)
Anticholinergics available for the treatment of OAB can either be nonselective or selective for one or more muscarinic receptor subtype (Table 1). This selectivity affects each drug’s tolerability profile because anticholinergic drugs that are not specific for the bladder can cause adverse effects such as dry mouth, con- stipation, blurred vision or cognitive impair- ment [Andersson, 2004].
Bladder
Imidafenacin is the most bladder-selective anticholinergic available: it antagonizes both the M3 and M1 receptor subtypes in vitro and in vivo [Kobayashi et al. 2007a, 2007b; Yamada et al. 2011b]. Furthermore, preclinical research
indicates that the duration of receptor binding of imidafenacin is longer in the bladder than in the salivary glands, heart, colon and brain [Kobayashi et al. 2007a, 2007b; Yamada et al. 2011b].
Brain
Imidafenacin does not bind to muscarinic recep- tors in the brain. After intravenous administration in rats, neither imidafenacin nor darifenacin showed significant binding to muscarinic recep- tors in the brain whereas an injection of oxybu- tynin was associated with brain muscarinic receptor binding [Yoshida et al. 2010]. In contrast to oxybutynin, imidafenacin also did not reduce cognitive function in a Morris water maze task in rats [Kobayashi et al. 2007b].
Similar findings have been reported in clinical studies. In patients with OAB due to neurological diseases, imidafenacin increased bladder volume at first sensation together with increasing oxy- hemoglobin concentration in the frontal micturi- tion area, with no cognitive decline [Sakakibara et al. 2011]. Furthermore, imidafenacin has been used effectively and safely for the treatment of OAB in patients with chronic stroke indicating that imidafenacin is associated with a good safety profile in neurological disorders [Kaneko et al.
2011].
Finally, while cognitive adverse events with the anticholinergic tolterodine are rare because it has limited entry into the brain, some cases of central nervous system adverse events have been reported [Diefenbach et al. 2008]. A retrospective analysis showed that these central nervous system adverse events are associated with mutations on one or both cytochrome P450 2D6 (CYP2D6) alleles [Diefenbach et al. 2008]. Unlike tolterodine, imidafenacin is not metabolized by CYP2D6 [Kanayama et al. 2007], so central nervous sys- tem adverse events are not expected.
Heart
Normally, the muscarinic M2 receptor subtype mediates a decrease in heart rate, which is associ- ated with bradycardia and decreased cardiac out- put [Andersson, 2004]. Therefore, antagonism of M2 receptors may lead to an increase in heart rate [Andersson, 2004], as seen for propiverine, an anticholinergic which nonselectively inhibits M2 [Abrams et al. 2006]. In comparison, imi- dafenacin does not appear to have any effect on the heart.
In a phase III, randomized controlled trial investigating the efficacy and tolerability of imi- dafenacin 0.1 mg twice daily and propiverine 20 mg/day in patients with OAB, there was no sig- nificant change from baseline in the QTc inter- val in imidafenacin recipients (–1.37 ± 21.53 ms), whereas propiverine was associated with a significant increase in the QTc interval (+7.56 ± 20.08 ms; p < 0.0001) [Homma and Yamaguchi, 2009]. Furthermore, imidafenacin was not asso- ciated with a significant change from baseline in heart rate; whereas heart rate significantly (p <
0.0001) increased in patients receiving propiv- erine (–0.8 ± 9.6 beats per minute [bpm] versus
+4.4 ± 9.2 bpm) [Homma and Yamaguchi,
2009].
Salivary
Imidafenacin is a potent inhibitor of salivary secretion. A preclinical study showed that imi- dafenacin was associated with a strong inhibition of the acetylcholine-induced K+ efflux from the salivary gland: only darifenacin was associated with more effective inhibition (darifenacin > imi- dafenacin > oxybutynin ≥ tolterodine > pirenze- pine ≥ propiverine > methoctramine) [Kobayashi et al. 2007a]. Furthermore, imidafenacin potently and dose-dependently inhibited carbamylcholine- stimulated salivary secretion in rats [Kobayashi et al. 2007b]. Again, only darifenacin was associ- ated with more effective inhibition [Kobayashi et al. 2007b]. However, this study also indicated that, while imidafenacin potently inhibits salivary secretion, it has an 8.8-fold preference for the muscarinic receptors in the bladder responsible for distention-induced rhythmic bladder contrac- tion (desired effect) over the muscarinic receptors responsible for salivary secretion (associated with dry mouth).
The selectivity of imidafenacin for the salivary gland was demonstrated in humans in a study conducted in 18 medical centers in Tokyo. This study showed that while imidafenacin was associ- ated with the shortest amount of time to the development of dry mouth, it was associated with the fastest resolution of dry mouth symptoms 1 month after drug administration, compared with solifenacin, tolterodine or propiverine [Kase et al. 2010].
Colon
The standard dose of imidafenacin (0.1 mg twice daily) shows little to no binding to muscarinic receptors in the colon whereas higher doses of imidafenacin have a short duration of binding to the colon [Yamada et al. 2011a]. In comparison, while low-dose tolterodine does not bind to mus- carinic receptors in the colon, high-dose toltero- dine is associated with a long duration of binding to these muscarinic receptors [Yamada et al.
2011a]. Tolterodine is generally well tolerated with low rates of constipation reported [Takei and Homma, 2005]; however, in patients who are low metabolizers, the long duration of binding in the colon may lead to significant gastrointestinal adverse events.
Imidafenacin has a short half-life and has a short duration of muscarinic receptor binding, which leads to a period of time between imidafenacin
administrations (a ‘resting phase’) when the drug has no antimuscarinic action in the colon. In comparison, anticholinergics with a long duration of muscarinic receptor binding, like solifenacin or propiverine, have no such ‘resting phase’.
Furthermore, solifenacin is associated with a long duration of binding to the colon and propiverine has been shown to bind to muscarinic receptors in the colon longer than in the bladder which increases the risk of these drugs, inducing consti- pation [Yamada et al. 2011a].
The timing of constipation also differs among anticholinergics. Time-dependent differences in the severity and incidence of adverse events between imidafenacin and solifenacin were observed in the LIST study (see efficacy and tol- erability section for trial details) [Zaitsu et al.
2011]. While there was no difference in the inci- dence of constipation between imidafenacin and solifenacin in patients who received treatment for at least 12 weeks (log rank test: p = 0.0621) (data on file), the incidence of constipation over the long term (52 weeks) was significantly higher in solifenacin recipients (log rank test: p = 0.0017) [Zaitsu et al. 2011].
Meek and colleagues conducted a meta-analysis investigating the relationship between anticholin- ergics used for the treatment of OAB and consti- pation [Meek et al. 2011]. They reported that the risk of constipation differed among drugs, and this variation may depend on differences in affin- ity for muscarinic receptors [Meek et al. 2011].
Of the anticholinergics analyzed (darifenacin, fesoterodine, oxybutynin, trospium, solifenacin and tolterodine), solifenacin was associated with the highest risk of constipation [odds ratio (OR) compared with placebo 3.02, 95% confidence interval (CI) 2.37–3.84], whereas tolterodine was associated with the lowest risk of constipation (OR 1.36, 95% CI 1.01–1.85) [Meek et al. 2011].
Efficacy and tolerability Primary clinical trials
Key clinical trial design features and outcomes for studies investigating the use of imidafenacin in OAB are summarized in Table 3.
Phase II. One phase II, randomized, double- blind, placebo-controlled, dose-finding study investigating the efficacy and tolerability of imi- dafenacin was conducted in 401 Japanese patients
with OAB [Homma et al. 2008]. Patients were randomized to oral imidafenacin 0.05, 0.1 and 0.25 mg twice daily or placebo.
Imidafenacin reduced urgency incontinence, voiding frequency and urinary urgency compared with placebo. Furthermore, the number of incon- tinence episodes (primary endpoint) in patients receiving imidafenacin 0.1 and 0.25 mg twice daily was significantly and dose-dependently reduced (p < 0.0001) compared with placebo [Homma et al. 2008].
Imidafenacin was generally well tolerated, with the incidences of adverse events following a dose- dependent pattern [Homma et al. 2008]. The most common adverse event was dry mouth.
Constipation, nasopharyngitis, abnormal sensa- tions in the eye, dyspepsia, dizziness and vomiting were also reported [Homma et al. 2008].
Considering the balance between the efficacy and safety of imidafenacin, a dose of 0.1 mg twice daily appeared to be a clinically appropriate dose for treating OAB. This dose was therefore selected for further evaluation in large-scale phase III studies.
Phase III. Three phase III trials investigating imidafenacin for the treatment of OAB have been published [Homma and Yamaguchi, 2008, 2009;
Yamaguchi and Homma, 2009]. The first was a randomized, double-blind, placebo- and propiv- erine-controlled trial which investigated the efficacy and tolerability of imidafenacin in 781 Japanese patients with OAB [Homma and Yamaguchi, 2009]. Patients were randomized to oral imidafenacin 0.1 mg twice daily, oral propiv- erine 20 mg once daily or placebo.
This study showed that imidafenacin was not inferior to propiverine for the reduction of incon- tinence episodes. Imidafenacin and propiverine significantly reduced the number of incontinence episodes per week versus placebo (–68.24% and –73.09% versus –49.50%, respectively; both p <
0.0001) [Homma and Yamaguchi, 2009]. Similar reductions in urgency incontinence, voiding fre- quency and urinary urgency were also observed in patients who received imidafenacin and propiver- ine. Imidafenacin was well tolerated and associ- ated with a significantly lower incidence of adverse events compared with propiverine (p = 0.0101) [Homma and Yamaguchi, 2009]. The most com- mon adverse event was dry mouth: reported in
Table 3. Summary of the efficacy and tolerability of imidafenacin in key clinical trials investigating imidafenacin for the treatment of overactive bladder. Study Study design, patient population and char
acteristics (n)
Dosage of imidaf
enacinComparator (compound, dosage)
Treatment durationPrimary clinical findingSafety summary
Dose- finding study [Homma et al. 2008]
Phase II, DB, PC, MC, R trial in men and women with OAB (401) 0.05 mg oral twice a day 0.1 mg oral twice a day 0.25 mg oral twice a day
pbo12 weeks
Mean change from baseline in the number of incontinence episodes per week at 12 weeks (%)
Any AE (%) 0.05 0.1 0.25pbo 0.05 0.1 0.25pbo –59.81–71.61*–82.19*–42.8665.766.084.255.4
Mean change from baseline in the number of urgency incontinence episodes per week at 12 weeks (%)
Dry mouth (%) 0.05 0.1 0.25pbo 0.05 0.1 0.25pbo –57.07–75.67*–74.20–18.9416.224.050.5 9.9
Mean change from baseline in the number of micturitions per day at 12 weeks
Nasopharyngitis (%) 0.050.10.25pbo 0.05 0.1 0.25pbo –1.72 –1.59 –2.33*–1.0713.110.0 9.913.9 Mean change from baseline in the urine volume voided per micturition at 12 weeks (ml)
Constipation (%) 0.05 0.1 0.25pbo 0.05 0.1 0.25pbo 14.06 9.8926.11*2.29 2.0 9.0 8.9 4.0
Phase III study [Homma and Yamaguchi, 2009]
Phase III, DB, PC, MC, AC, R trial in men and women with OAB (781) 0.1 mg oral twice a day Pbo propiverine 20 mg oral once a day
12 weeks
Mean change from baseline in the number of incontinence episodes per week at 12 weeks (%)
Any AE (%) imipropboimipropbo –68.24*–73.09*–49.5072.981.768.3
Mean change from baseline in the number of urgency incontinence episodes per week at 12 weeks (%)
Dry mouth (%)
Study Study design, patient population and char
acteristics (n)
Dosage of imidaf
enacinComparator (compound, dosage)
Treatment durationPrimary clinical findingSafety summary imipropboimipropbo –69.47*–75.53*–49.2331.539.913.8
Mean change from baseline in the number of micturitions per day at 12 weeks
Nasopharyngitis (%) imipropboImipropbo –1.52$ –1.80$–1.0818.419.923.4
Mean change from baseline in the urine volume voided per micturition at 12 weeks (ml)
Constipation (%) ImipropboImipropbo 19.35*36.07*9.2811.813.7 7.6
Long term study [Homma and Yamaguchi, 2008]
Phase III, OL, MC trial in men and women with OAB (478) 0.1 mg oral twice a day
N/A52 wks
Mean change from baseline in the number of incontinence episodes per week at 52 weeks (%)
Any AE at 52 weeks (%) –83.51$90.4
Mean change from baseline in the number of urgency incontinence episodes per week at 52 weeks (%)
Dry mouth (%) –84.21$40.2
Mean change from baseline in the number of micturitions per day at 52 weeks
Nasopharyngitis (%) –2.35$30.8
Mean change from baseline in the urine volume voided per micturition at 52 weeks (ml)
Constipation (%) 28.99$14.4
Table 3. (Continued) (Continued)
Study Study design, patient population and char
acteristics (n)
Dosage of imidaf
enacinComparator (compound, dosage)
Treatment durationPrimary clinical findingSafety summary
Dose increase study [Yamaguchi and Homma, 2009]
Phase III, OL, MC trial in men and women with OAB (435) 0.1 mg oral twice a day 0.2 mg oral twice a day
N/A52 weeks
Mean change from baseline in the number of urgency incontinence episodes per week at 64 weeks (%)
Dry mouth (%) 0.1mg bid0.2mg bid 0.1 mg twice a day0.2 mg twice a day26.553.3 64 weeksConstipation (%) NR–77.85
0.1 mg twice a day 0.2 mg twice a day
9.918.7 *Significant difference (p≤ 0.05) versus placebo. $Significant difference (p< 0.05) versus baseline AC, active control; AE, adverse event; CO, crossover; DB, double blind; imi, imidafenacin; MC, multicenter; N/A, not applicable; NR, not reported; OAB, overactive bladder; OL, open label; pbo, placebo; PC, placebo controlled; PG, parallel group; pro, propiverine; R, randomized.
Table 3. (Continued)
31.5% and 39.9% of patients receiving imidafena- cin and propiverine, respectively (p = 0.0302).
An open-label study investigating the long-term tolerability and efficacy of imidafenacin 0.1 mg twice daily showed that the favorable safety, toler- ability and efficacy observed with imidafenacin was maintained over 52 weeks in 478 Japanese patients with OAB [Homma and Yamaguchi, 2008]. Again, the most commonly reported adverse event was dry mouth (40.2% of patients) [Homma and Yamaguchi, 2008]. In this study, 41 serious adverse events and one death in 35 patients were reported [Homma and Yamaguchi, 2008]. Forty of the serious adverse events were considered not related to the study drug; whereas one serious adverse event (acute glaucoma) was considered possibly related to imi- dafenacin [Homma and Yamaguchi, 2008]. The death (ischemic cardiac failure resulting from con- current hypertension) was considered not related to the study drug [Homma and Yamaguchi, 2008].
Another open-label study investigating the long- term tolerability and efficacy of imidafenacin 0.2 mg twice daily was conducted in 435 Japanese patients with OAB who did not have an adequate respond to imidafenacin 0.1 mg twice daily [Yamaguchi and Homma, 2009]. At the higher dosage, imidafenacin was relatively well tolerated, with dry mouth and constipation reported in 53.3% and 18.7% of patients receiving 0.2 mg twice daily and 26.5% and 9.9% of patients receiving 0.1 mg twice daily, respectively [Yamaguchi and Homma, 2009]. Furthermore, imidafenacin 0.2 mg twice daily improved the number of urgency incontinence episodes per week after 16 weeks of treatment compared with 0.1 mg twice daily [Yamaguchi and Homma, 2009]. The authors concluded that if the effect of imidafenacin 0.1 mg twice daily is insufficient, a dose increase to 0.2 mg twice daily could be effec- tive and safe, providing additional options for managing patients who are not satisfied with the effect of the standard dose of imidafenacin [Yamaguchi and Homma, 2009].
Other clinical trials
Overactive bladder. The LIST study was a ran- domized, open-label, 52-week study comparing the efficacy and tolerability of imidafenacin (0.1 mg twice daily) and solifenacin (5 mg once daily) in patients with OAB [Zaitsu et al. 2011].
The results showed no significant difference
between the two anticholinergics in terms of effi- cacy over 12 and 52 weeks, but the severity and incidence of drug-induced adverse events differed between treatment groups (Table 4) [Zaitsu et al.
2011]. The severity of dry mouth associated with imidafenacin was significantly milder than that in solifenacin recipients: four patients (20%) receiv- ing solifenacin reported severe dry mouth com- pared with none receiving imidafenacin [Zaitsu et al. 2011]. Furthermore, the incidence of constipa- tion was also significantly (p = 0.0013) lower with imidafenacin than solifenacin [Zaitsu et al. 2011].
The authors proposed that the differences in the observed tolerability of these two anticholinergics may be due to differences in pharmacokinetics and binding selectivity [Zaitsu et al. 2011].
Nocturia. Nocturia, the need to get up in the night to urinate, is a common symptom of OAB.
A number of studies investigating the effects of imidafenacin on nocturia and sleep quality have been conducted [Takeda et al. 2009; Nagaoka et al. 2011; Shimizu et al. 2011; Kuratsukuri et al.
2012], which highlight that imidafenacin is a via- ble option for improving sleep quality and dura- tion in patients with OAB and nocturia.
The Evaluation of Anticholinergics in Patients with OAB and Nocturia for Cared-health (EPOC) study investigated the effects of imidafenacin 0.1 mg twice daily on sleep in patients with OAB [Takeda et al. 2009]. This study found that after 8 weeks of treatment there was a correlation between the improvement observed in nocturia, assessed using a frequency volume chart, and sleep quality, assessed using the Pittsburgh Sleep Quality Index (PSQI; correlation coefficient 0.358) [Takeda et al. 2009].
This was supported by the FUSION study which investigated the effects of imidafenacin on sleep disorders and health-related quality of life (HRQOL) in patients with OAB and noc- turia [Nagaoka et al. 2011]. Imidafenacin was associated with improved sleep parameters and HRQOL.
The GOOD-NIGHT study investigated the efficacy and tolerability of imidafenacin and α-blocker therapy in men with benign prostatic hyperplasia and OAB [Kuratsukuri et al. 2012].
This open-label study in 130 men who had been receiving an α-blocker for at least 4 weeks and were experiencing nocturia randomized patients to an α blocker alone, an α blocker with
Table 4. Summary of the LIST study by Zaitsu and colleagues [Zaitsu et al. 2011].
Study The LIST Study (Japan University Hospital Medical Information Network record number UMIN000004354) [Zaitsu et al. 2011]
Study design Open, randomized, parallel group, active controlled Patient
population and characteristics (n)
Japanese patients with untreated overactive bladder (n = 41)
Age: ≥50 to <80 years (mean 70 years) Treatment
details Imidafenacin 0.1 mg twice daily (n = 21)
Discharged from the study due to lack of response, tolerability or other issues (n = 4) Comparator Solifenacin 5 mg/day (n = 20)
Discharged from the study due to lack of response, tolerability or other issues (n = 2) Treatment
duration 52 weeks
Result summary Imidafenacin Solifenacin p value
baseline 52 weeks baseline 52 weeks
OABSS 9.0 ± 1.3 4.3 ± 2.8 8.9 ± 2.6 5.1 ± 2.1 0.6384
KHQ Imidafenacin significantly improved all KHQ subscores from baseline. These improvements were similar to those observed with solifenacin
AE summary (%
patients) Imidafenacin Solifenacin p value
Any AE 76.2 95.0
Dry mouth 71.4 90.0 0.2379
Constipation 14.3 65.0 0.0013
Blurred vision 9.5 35.0 0.0670
Time to first AE at 52 weeks:
Dry mouth the time to the first adverse event caused by solifenacin increased after 12 weeks, but not by imidafenacin(log rank test: p = 0.0412).
Constipation the time to the first adverse event caused by solifenacin increased after 12 weeks, but not by imidafenacin(log rank test: p = 0.0017).
Blurred vision No significant difference between treatment groups (log rank test: p = 0.0686) AE, adverse event; KHQ, King’s Health Questionnaire; OABSS, overactive bladder symptoms score.
imidafenacin 0.1 mg twice daily or an α blocker with imidafenacin 0.1 mg once daily [Kuratsukuri et al. 2012]. Adding imidafenacin 0.1 mg twice daily and 0.1 mg once daily (administered in the evening) to α-blocker therapy was associated with a reduction in night-time voiding (p = 0.0014 and 0.0143) and an improvement in Nocturia Quality Of Life Questionnaire scores (p = 0.0013 in imi- dafenacin 0.1 mg twice daily group only) after 8 weeks of treatment compared with α-blocker ther- apy alone [Kuratsukuri et al. 2012].
Finally, a study in 140 older patients with OAB showed that imidafenacin 0.1 mg twice daily improved nocturnal polyuria after 4 weeks of treatment [Shimizu et al. 2011]. In patients aged 65–74 years and patients aged at least 75 years,
imidafenacin was associated with a significant (p < 0.001) reduction in the Overactive Bladder Symptom Score (OABSS) [Shimizu et al. 2011].
Benign prostatic hyperplasia. Imidafenacin has demonstrated utility for the management of symptoms in patients with benign prostatic hyperplasia and OAB. The GOOD-NIGHT study found that adding imidafenacin 0.1 mg twice daily and 0.1 mg once daily to α-blocker therapy not only improved nocturia (as dis- cussed previously) but was also associated with an improvement in International Prostate Symp- tom Score Quality of Life (IPSS-QOL) scores (p = 0.0040 and 0.0038) after 8 weeks of treat- ment compared with α-blocker therapy alone [Kuratsukuri et al. 2012].
Women. Imidafenacin improved OAB symptoms and quality of life, assessed using the OABSS and the International Consultation on Incontinence Questionnaire – Short Form, respectively, in a trial investigating the efficacy and safety of imidaf- enacin in women with urge and mixed urinary incontinence [Shimada et al. 2011b]. Imidafena- cin was also well tolerated [Shimada et al. 2011b]:
no serious adverse events were reported and the incidence of any adverse event was low (7.9%).
Older people. Unpublished results from phase II and phase III, double-blind, placebo-controlled trials indicate that age does not appear to influ- ence the efficacy or tolerability of imidafenacin.
Furthermore, in a prospective clinical trial in 140 patients with OAB who received imidafena- cin 0.1 mg twice daily for 4 weeks, there was no difference between patients aged 65–74 years old and patients aged at least 75 years with regards to the reduction in OABSS scores (from 8.5 ± 3.2 to 5.2 ± 3.4 and from 8.9 ± 3.0 to 5.5 ± 3.1, respec- tively; both p < 0.001) [Shimizu et al. 2011].
Clinical benefits of imidafenacin: a summary Imidafenacin is clinically effective
Imidafenacin has been shown to be a potent anticholinergic in in vitro studies [Kobayashi et al.
2007a, Yamada et al. 2011b]. Furthermore, in a phase III clinical trial, imidafenacin was associ- ated with a significant improvement in OAB compared with placebo: this benefit was similar (not inferior) to the efficacy of propiverine 20 mg/
day in this trial [Homma and Yamaguchi, 2009].
Imidafenacin is also associated with a similar efficacy to solifenacin. In the Global Assessment Study of Anti-cholinergics on Efficacy and Tolerability for Patients with OAB study, both imidafenacin and solifenacin were associated with significant improvements in the total and four subscores of the OABSS [Nishii et al. 2011]:
the LIST study showed similar results [Zaitsu et al. 2011]. Finally, the efficacy of imidafenacin for the treatment of OAB is immediate: efficacy is observed 3 days after the initiation of treatment [Kubota et al. 2010; Kitagawa et al. 2011].
Imidafenacin is safe and well tolerated for long-term treatment
Studies have demonstrated that imidafenacin is associated with a favorable short-term tolerability profile compared with propiverine [Homma and
Yamaguchi, 2009] and a favorable long-term tol- erability profile compared with solifenacin [Zaitsu et al. 2011]. In addition, in a study conducted by Kase and colleagues, imidafenacin was associated with the shortest duration of dry mouth symp- toms compared with other anticholinergics [Kase et al. 2010].
Adjustable dosing
One unique feature of imidafenacin treatment is the ability to easily adjust dosing. Some patients with OAB only experience symptoms during part of the day. Imidafenacin is given as a twice-daily oral tablet and this enables treatment to be admin- istered at a time most suitable to target the symp- toms when they happen. For example, in patients with nocturia, 0.3 mg/day imidafenacin can be administered as 0.1 mg in the morning and 0.2 mg in the evening. Furthermore, a new oral disinte- grating tablet formulation has been developed that allows for administration without water [Shimada et al. 2011a], which could help patients to control drinking behavior and limit fluid intake.
Conclusions
OAB is a chronic disease. Therefore, the ideal treatment should have good long-term efficacy and tolerability. Imidafenacin meets these crite- ria, making it is a useful anticholinergic for the treatment of OAB.
Acknowledgements
We thank Simone Boniface of inScience Communications, Springer Healthcare, who provided copyediting and journal styling prior to submission. We are grateful for the help and support of our colleague at Kanto Rosai Hospital for the LIST study.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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