A randomized,double‐blind,placebo‐controlled phase II dose‐finding study of the novel anti‐muscarinic agent imidafenacin in Japanese patients with overactive bladder

Objectives: To evaluate the efficacy, safety/tolerability, and dose–response relationship of imidafenacin in Japanese patients with overactive bladder. Methods: Men and women who had overactive bladder symptoms were randomized equally to double‐blind treatment with 0.05, 0.1, or 0.25 mg of imidafenacin twice daily or a placebo for 12 weeks, and assessed for efficacy and safety. Results: Overall, 401 patients were enrolled and randomized for treatment with 0.1 mg of imidafenacin/day (99 patients), 0.2 mg of imidafenacin/day (100), 0.5 mg of imidafenacin/day (101), or a placebo (101). After 12 weeks of treatment, the number of incontinence episodes was reduced in a dose‐dependent manner, and a significant difference between the imidafenacin treatment and the placebo was observed (P < 0.0001). Compared with the placebo, imidafenacin caused significant reductions in urgency incontinence, voiding frequency, and urinary urgency, and a significant increase in the urine volume voided per micturition. Imidafenacin was also well tolerated. The incidence of dry mouth in the imidafenacin groups increased dose‐dependently. Even though the percentage of patients receiving 0.5 mg/day who discontinued treatment due to dry mouth was high (8.9%), the percentages in the 0.1 mg/day and 0.2 mg/day groups (1.0% and 0.0%, respectively) were comparable with that in the placebo group (0.0%). Conclusions: Considering the balance between efficacy and safety, 0.1 mg of imidafenacin twice daily appeared to be a clinically appropriate dose for treating overactive bladder. This dose was therefore selected for further evaluation in large‐scale phase III studies.     

Imidafenacin for the treatment of overactive bladder

Introduction: Imidafenacin (KRP-197/ONO-8025) is the latest antimuscarinic (AM) developed for the treatment of overactive bladder syndrome (OAB) and, at the moment, it is marketed only in Japan. This compound has been developed to improve the tolerability of AM therapy by binding specifically the M₃ receptor subtype, thus limiting undesirable adverse events (AEs).

Areas covered: This systematic review offers a brief explanation of the mechanism of action and of the pharmacokinetics of imidafenacin and helps readers to understand the clinical efficacy, tolerability, and safety of the compound in the setting of OAB therapy.

Expert opinion: Imidafenacin is an AM drug with excellent efficacy, tolerability, and safety. It is indicated for patients with nocturia, nocturnal polyuria, and benign prostatic hyperplasia. This compound, due to its pharmacokinetic properties, gives the opportunity to be easily adjusted in its dosages. Further studies should assess the pharmacokinetics, clinical efficacy, safety, and tolerability of imidafenacin in Caucasian and African populations because this AM agent, at the moment, has been evaluated just in Asian populations. More studies should evaluate and compare efficacy, safety, and tolerability of imidafenacin also with other largely utilized AMs, such as oxybutynin, tolterodine, and fesoterodine, or with the other M3 selective compound, darifenacin.     

咪达那新的合成工艺研究

目的 对咪达那新的合成工艺进行研究。方法 以二苯乙腈为起始原料,与1,2-二溴乙烷经相转移反应生成4-溴-2,2-二苯基丁腈（1）,化合物1在三乙胺存在下,于N,N-二甲基甲酰胺–二甲基亚砜中与2-甲基咪唑反应,生成4-(2-甲基-1H-咪唑-1-基)-2,2-二苯基丁腈（2）,化合物2在70%硫酸溶液中,经水解、精制得咪达那新。结果 该合成工艺总收率为40.2%,终产物质量分数为99.9%。结论 工艺改进后,简化了操作过程,提高了咪达那新的收率。     

咪达那新片在中国健康受试者生物等效性研究

目的 研究咪达那新片仿制药与原研药在中国健康受试者中单剂量空腹和餐后条件下给药的生物等效性.方法 采用单中心、随机、开放、单次给药、两制剂、两周期交叉试验设计,共纳入60例(空腹试验30例,餐后试验30例)成年男性和女性受试者随机交叉给药.分别单次口服受试制剂和参比制剂0.1 mg,用液相色谱串联质谱法(LC/MS/M...     

咪达那新及其主要有关物质的合成

二苯乙腈与1,2-二溴乙烷经取代,与2-甲基咪唑缩合制得4-(2-甲基-1H-咪唑-1-基)-2,2-二苯基丁腈(6),6成盐酸盐后用氢氧化钾水解得咪达那新,总收率51.2％,HPLC纯度为99.5％.咪达那新在氢氧化钾水解下制得主要有关物质4-(2-甲基-1H-咪唑-1-基)-2,2-二苯基丁酸,HPLC纯度为98％.     

A randomized, double-blind, placebo- and propiverine-controlled trial of the novel antimuscarinic agent imidafenacin in Japanese patients with overactive bladder

Objectives:   To compare the efficacy and tolerability of imidafenacin, a novel antimuscarinic agent, with propiverine and a placebo in Japanese patients with overactive bladder (OAB).
Methods:   Men and women having OAB symptoms were randomized to double-blind treatment with 0.1 mg of imidafenacin twice daily, 20 mg of propiverine once daily, or a placebo for 12 weeks, and assessed for efficacy and safety.
Results:   Overall, 781 patients were randomized to imidafenacin (324), propiverine (310), or a placebo (147). After 12 weeks of treatment, a significantly larger reduction in the mean number of incontinence episodes was observed in the imidafenacin group than in the placebo group ( P  < 0.0001). The non-inferiority of imidafenacin compared with propiverine was confirmed for the reduction in using incontinence episodes ( P  = 0.0014, non-inferiority margin: 14.5%). Imidafenacin was well tolerated. The incidence of adverse events with imidafenacin was significantly lower than with propiverine ( P  = 0.0101). Dry mouth, the most common adverse event, was significantly more common in the propiverine group than in the imidafenacin group ( P  = 0.0302). There were no significant increases in either the imidafenacin or placebo group in the mean QTc interval, whereas there was a significant increase in the mean QTc interval in the propiverine group ( P  < 0.0001), but there were no clinical arrhythmia and clinical arrhythmic events in any of the treatment groups.
Conclusions:   The novel antimuscarinic agent imidafenacin at a dose of 0.1 mg twice daily was not inferior to propiverine for the reduction of incontinence episodes, and well tolerated for the treatment of OAB symptoms.     

Quantitative analysis of pseudopolymorphic transformation of imidafenacin by application of a novel combination of near-infrared spectroscopy and a humidity-controlled 96-well plate

Objectives This study was conducted to test whether our novel combination (i.e. microanalysis) of near‐infrared (NIR) spectroscopy and humidity‐controlled 96‐well plate, reported in a previous issue of this journal, can be successfully applied to quantitative evaluation of the pseudopolymorphic transformation of imidafenacin. Methods Sample powders of a drug compound were placed in a humidity‐controlled 96‐well plate containing various saturated salt solutions, and stored at 35°C. NIR spectra were collected using a Fourier transform‐NIR spectrometer in combination with a fiber‐optic probe. The actual hydrate contents of samples were determined by using thermal gravimetric analysis (TGA). A series of sets of NIR spectra and TGA data were used to establish a calibration model with which to predict the contents of monohydrate by partial least‐squares regression (PLS). Key findings The PLS calibration model analysis showed that the plots of NIR predicted values to the actual values gave a straight line with correlation coefficients of 0.9868 and 0.9936, respectively, for the 96‐well plate and glass‐bottle uses. The model using the 96‐well plate was therefore able to predict the transformation of imidafenacin in one form to another form as quantitatively as the conventional model using glass bottles. Conclusion The present study confirmed that our microanalysis quantitatively predicts the pseudopolymorphic transformation of our tested drug in small amounts and suggests that this particular method is a simple and convenient one that may be efficiently applied to polymorphic and pseudopolymorphic studies of a hygroscopic drug candidate, at even earlier development stages than the conventional method using glass bottles.     

Muscarinic Receptor Binding of Imidafenacin in the Human Bladder Mucosa and Detrusor and Parotid Gland

Objectives: The current study aimed to characterize comparatively the binding of imidafenacin to muscarinic receptors in the human bladder mucosa and detrusor muscle and parotid gland. Methods: The muscarinic receptor in homogenates of human tissues (bladder mucosa and detrusor muscle and parotid gland) was measured using a radioligand binding assay with [N‐methyl‐³H]scopolamine methyl chloride ([³H]NMS). Results: Imidafenacin competed with [³H]NMS for binding sites in the bladder mucosa and detrusor muscle and parotid gland, and its affinity was significantly (2.6–8.7 times) higher than that of oxybutynin. Also, the affinity of imidafenacin for muscarinic receptors was approximately two‐fold higher in the parotid gland than bladder tissue. The affinity of imidafenacin in the mucosa was similar to that in the detrusor muscle, suggesting that this agent exhibits therapeutic effects by blocking muscarinic receptors in the mucosa as well as detrusor muscle. Scatchard analysis revealed that imidafenacin increased significantly (approximately four‐fold) K_d values for [³H]NMS binding in the human detrusor muscle and parotid gland, with little effect on B_max values. This observation indicates that imidafenacin binds to the muscarinic receptors in human tissues in a competitive and reversible manner. Conclusion: Imidafenacin binds to muscarinic receptors in the human bladder mucosa and detrusor muscle and parotid gland with high affinity. This agent was considered to exhibit therapeutic effects on the lower urinary tract symptoms due to an overactive bladder by blocking muscarinic receptors in the urothelium as well as detrusor muscle.     

Effect of Imidafenacin before Sleeping on Nocturia

Objectives: Clinical efficacy, influence on quality of life (QOL), and safety of imidafenacin before sleeping were assessed in patients with overactive bladder (OAB) who suffered from nocturia. Methods: A total of 60 OAB patients with a mean age of 74 years (45 men and 15 women) who mainly complained of nocturia were enrolled. Imidafenacin (0.1 mg) was administered once daily before sleeping for four weeks. Then the patients were divided into two groups, “a stable‐dose group” with sufficient efficacy who remained on 0.1 mg of imidafenacin daily, and “a dose‐escalation group” with insufficient efficacy in whom the daily dose of imidafenacin was increased to 0.2 mg before sleeping. Lower urinary tract symptoms and postvoid residual volume (PVR) were examined before treatment and after 4 and 8 weeks of imidafenacin therapy. Results: In the stable‐dose group, nighttime frequency decreased significantly from 3.4 ± 1.1 to 2.3 ± 1.1 and 2.6 ± 2.0 times after four and eight weeks, respectively. In the dose‐escalation group, nighttime frequency did not change significantly (from 3.8 ± 1.5 to 3.6 ± 1.8 times) at four weeks, but decreased significantly to 2.8 ± 1.4 times at eight weeks. Daytime frequency, OAB symptom score, and IPSS‐QOL index score were significantly improved in both groups at four and/or eight weeks. There was no increase of PVR and no serious adverse events. Conclusion: Administration of imidafenacin at 0.1–0.2 mg once daily before sleeping was safe and effective for the treatment of OAB with the main symptom of nocturia.