Mirabegron and Anticholinergics in the Treatment of Overactive Bladder Syndrome: A Meta-analysis / Mirabegron e anticolinérgicos no tratamento da síndrome da bexiga hiperativa: metanálise

Abstract Objective To compare the use of mirabegron with anticholinergics drugs for the treatment of overactive bladder (OB). Data Source Systematic searches were conducted in EMBASE, PUBMED, Cochrane, and LILACS databases from inception to September 2021. We included RCTs, women with clinically proven OB symptoms, studies that compared mirabegron to antimuscarinic drugs, and that evaluated the efficacy, safety or adherence. Data Collection RevMan 5.4 was used to combine results across studies. We derived risk ratios (RRs) and mean differences with 95% CIs using a random-effects meta-analytic model. Cochrane Collaboration Tool and GRADE was applied for risk of bias and quality of the evidence. Data Synthesis We included 14 studies with a total of 10,774 patients. Fewer total adverse events was reported in mirabegron group than in antimuscarinics group [RR 0.93 (0.89-0.98)]. The risk of gastrointestinal tract disorders and dry mouth were lower with mirabegron [RR 0,58 (0.48-0.68); 9375 patients; RR 0.44 (0.35-0.56), 9375 patients, respectively]. No difference was reported between mirabegron and antimuscarinics drugs for efficacy. The adherence to treatment was 87.7% in both groups [RR 0.99 (0.98-1.00)]. Conclusion Mirabegron and antimuscarinics have comparable efficacy and adherence rates; however, mirabegron showed fewer total and isolated adverse events.

Resumo Objetivo Comparar o uso de mirabegrom com anticolinérgicos para o tratamento da bexiga hiperativa (BH). Fonte de Dados Buscas sistemáticas foram realizadas nas bases de dados EMBASE, PUBMED, Cochrane e LILACS desde o início até setembro de 2021. Incluímos ECR, mulheres com sintomas de BH clinicamente comprovados, estudos que compararam mirabegrom a medicamentos antimuscarínicos e avaliaram a eficácia, segurança ou adesão. Coleta de Dados RevMan 5.4 foi usado para combinar os resultados entre os estudos. Derivamos razões de risco (RRs) e diferenças médias com intervalo de confiança (IC) de 95% usando um modelo meta-analítico de efeitos aleatórios. Cochrane Collaboration Tool e GRADE foi aplicado para risco de viés e qualidade da evidência. Síntese dos Dados Foram incluídos 14 estudos com um total de 10.774 pacientes. Menos eventos adversos totais foram relatados no grupo mirabegrom do que no grupo antimuscarínicos [RR: 0,93 (0,89-0,98)]. O risco de distúrbios do trato gastrointestinal e boca seca foram menores com mirabegrom [RR: 0,58 (0,48-0,68); 9.375 pacientes; RR: 0,44 (0,35-0,56), 9.375 pacientes, respectivamente]. Nenhuma diferença foi relatada entre mirabegrom e drogas antimuscarínicos para eficácia. A adesão ao tratamento foi de 87,7% em ambos os grupos [RR: 0,99 (0,98-1,00)]. Conclusão Mirabegrom e antimuscarínicos têm eficácia e taxas de adesão comparáveis, porém o mirabegrom apresentou menos eventos adversos totais e isolados.

Assessment of Prescribing Practices in Overactive Bladder Pharmacotherapy across Different Specialties of India : A Prescription Trend Analysis

Purpose : To assess the temporal prescription patterns of overactive bladder (OAB) pharmacotherapy based on the prescription trend analysis amongst Indian clinicians. Methods : IQVIA (Quintiles and IMS Health) secondary sales audit (SSA) and prescription audit for antimuscarinics and beta-3 adrenoceptor agonist (mirabegron) from 2014 to 2022, were analyzed. Prescribers overlap analysis for solifenacin and mirabegron among Indian urologists was also analyzed. Results : Urologists’ prescription rates of OAB drugs were 65% in 2016 and 52% in 2022. The rate of OAB medication prescription by non-urologists was highest among surgeons (17%), followed by consultant physicians (9%) and gynecologists (8%) in 2022. In addition, among OAB medication prescription rates for antimuscarinics were 100% in 2016 and 56% in 2022 whereas for mirabegron, it was 0% in 2016 and 44% in 2022. The proportion of prescribers of OAB medication among urologists was 38% in 2016 and 33% in 2022. Exclusive prescribers of solifenacin were 748 in 2018 and 715 in 2022 at the urologist, whereas for mirabegron, it was 961 in 2018 and 1475 in 2022. Conclusions : Urologists remained a top prescribing specialty for OAB drugs, although prescription share increased among surgeons and consultant physicians. OAB medicines prescriptions by urologists are shifting from solifenacin to mirabegron. The results of this study could further help clinicians, to design the optimum treatment approach in OAB patients according to their need, which can help to lower antimuscarinic side effects, improves treatment adherence, and improves patient’s QoL.

Costoefectividad del régimen combinado de mirabegron/solifenacina en el tratamiento del síndrome de vejiga hiperactiva en Colombia / Cost-effectiveness of the Combined Regimen of Mirabegron/Solifenacin in the Treatment of Overactive Bladder Syndrome in Colombia

Objetivo Evaluar la costoefectividad incremental del régimen combinado de mirabegron/solifenacina en comparación con el uso temprano de toxina botulínica, desde la perspectiva del sistema de salud colombiano, para el tratamiento de adultos con vejiga hiperactiva. Métodos Se empleó un modelo de Markov en que se comparan dos secuencias de tratamiento, una con y otra sin mirabegron/solifenacina, para evaluar la costoefectividad en un horizonte temporal de cinco años. Debido a la perspectiva de análisis, sólo se tuvieron en cuenta los costos médicos directos. La eficacia del tratamiento evaluado y su comparador fue medida en términos de la reducción de episodios diarios de incontinencia y de la frecuencia de micciones. Los costos fueron expresados en pesos colombianos de 2019, y se aplicó una tasa de descuento de 5% tanto para desenlaces como para costos. Resultados Para el caso base, el costo del tratamiento en la secuencia que incluye mirabegron/solifenacina fue mayor, pero generó un mayor número de años de vida ajustados por calidad, y así e obtuvo una razón de costoefectividad incremental de $13.637,184 si se considera el desenlace de reducción de episodios diarios de incontinencia de 50%, y de $29.313,848 si se considera el del 100%. Conclusiones De acuerdo con los resultados de esta evaluación, para un horizonte de análisis de cinco años, la secuencia de tratamiento con mirabegron/solifenacina es una alternativa costoefectiva, si se considera un umbral de disposición a pagar de tres veces el producto interno bruto (PIB) per cápita.

Aim To evaluate the incremental cost-effectiveness of the combined regimen of mirabegron/solifenacin compared with the early use of botulinum toxin, from the perspective of the Colombian health system, for the treatment of adults with overactive bladder. Methods A Markov model comparing two treatment sequences, one with and one without mirabegron/solifenacin, was used to assess cost-effectiveness over a five-year period. Due to the perspective of the analysis, only direct medical costs were considered. The efficacy of the evaluated treatment and its comparator was measured in terms of the reduction in the daily incontinence episodes and the frequency of micturition. The costs were expressed in Colombian pesos of 2019, and a discount rate of 5% was applied for both outcomes and costs. Results For the base case, the cost of the treatment in the sequence that includes mirabegron/solifenacin was higher, but it generated a greater number of quality-adjusted years of life, thus obtaining an incremental cost-effectiveness ratio of $13,637,184 when considering the outcome of 50% of reduction in the daily incontinence episodes, and $29,313,848 when considering 100%. Conclusions According to the results of the present assessment, for a five-year period of analysi, the mirabegron/solifenacin treatment sequence is a cost-effective alternative when considering a threshold of willingness to pay three times the per capita gross domestic product (GDP).

Mirabegron Role in Urolithiasis Management: What you should Know / Rol del mirabegrón en el manejo de la urolitiasis: Lo que usted debe saber

The purpose of the present study was to develop a narrative review of the available evidence of mirabegron efficacy in three scenarios: as a medical expulsive therapy; as a medical treatment to increase a successful access to stones before ureteroscopy, and management of double-J stent-related symptoms. Only two original studies have evaluated its use as a medical expulsive therapy, with contradictory results in terms of stone expulsion rate; however, both demonstrated a better pain control in the mirabegron group. One randomized controlled trial (RCT) found a higher successful access to ureteral stones when mirabegron was administered 1 week before the ureteroscopy. And two RCTs demonstrated its efficacy in diminishing discomfort related with double-J stent. There is a promising role for the use of mirabegron in the arsenal of urolithiasis treatment, even as a medical expulsive therapy, before ureteroscopy surgery, to increase the successful access to the stones and after the placement of ureteral catheter to reduce the related symptoms. However, larger-scaled prospective double-blinded RCTs are needed before it can be used with these purposes in the clinical scenario.

El propósito de este trabajo fue desarrollar una revisión narrativa de la literatura describiendo la evidencia disponible sobre la eficacia del mirabegrón en tres escenarios: como terapia médica expulsiva, como tratamiento médico antes de la ureteroscopia para incrementar el acceso exitoso al cálculo, y en el manejo de los síntomas asociados con el uso de catéter doble J. Solo dos estudios originales han evaluado su uso como terapia médica expulsiva, con resultados contradictorios en términos de tasa de expulsión del cálculo; sin embargo, ambos demostraron mejor control del dolor en el grupo de mirabegrón. Un estudio aleatorizado multicéntrico encontró un aumento en el acceso exitoso al cálculo durante la ureteroscopia cuando el mirabegrón era administrado una semana antes del procedimiento. Adicionalmente, dos estudios aleatorizados controlados demostraron eficacia del medicamento para disminuir los síntomas relacionados con el catéter doble J. El uso del mirabegrón como parte del arsenal del tratamiento para urolitiasis tiene un rol prometedor, tanto en la terapia médica expulsiva como antes de la ureteroscopia, para aumentar la posibilidad de acceder exitosamente al cálculo, y en pacientes con catéter doble J, para disminuir los síntomas asociados. Sin embargo, se requiere estudios más grandes, prospectivos, doble ciegos y aleatorizados antes de que podamos utilizarlo con estos fines en un escenario clínico.

Improvement of synthesis process of mirabegron / 中国药科大学学报

@#Overactive bladder is a syndrome characterized by urgent urination, often accompanied by frequent urination and nocturia. The incidence of the disease is high all over the world, and it has a great impact on the lives of patients, which has been paid more and more attention by scholars at home and abroad. It is currently estimated that 50 million to 100 million people worldwide suffer from the disease. Mirabegron is an agonist of human β-3 adrenergic receptor used to treat symptoms of overactive bladder. In this study, the synthesis process of mirabegron was improved based on literatures. Using p-nitrophenethylamine hydrochloride, R-(-)-mandelicacid and 2-aminothiazole-4-acetic acid as starting materials, the target product with high purity was obtained through four steps of amide condensation, carbonyl reduction, nitro reduction and amide condensation, and one-step purification, with a total yield of 39%. In this study, the hydrogen source of nitro reduction in step 3 was changed from hydrogen to ammonium formate, which increased the feasibility of industrialization, and mirabegron was refined to improve the purity of the product. The improved process has the advantages of simplified operation and mild reaction conditions, which provides a new method for the preparation and purification of mirabegron.

Efficacy and tolerability of mirabegron in female patients with overactive bladder symptoms after surgical treatment for stress urinary incontinence

ABSTRACT Purpose To evaluate the efficacy and tolerability of mirabegron in females with overactive bladder (OAB) symptoms after surgical treatment for stress urinary incontinence (SUI). Materials and Methods The study was conducted with a prospective, randomized and double-blinded design. 62 patients over the age of 40 who met the inclusion-exclusion criterias of the study were enrolled and randomly divided into two groups as Group A (mirabegron 50mg) and B (solifenacin 5mg). Patients were compared based on efficacy of treatment [Patient Perception of Bladder Condition (PPBC) scale and micturition diaries], safety of treatment (heart rate, systolic and diastolic blood pressure, adverse events), number of micturitions per day, patient's satisfaction status after treatment [Visual Analog Scale(VAS)] and quality of life. Results The mean age of the population was 48.2±3.8 years and the duration of OAB symptoms was 5.9±2.9 months. Baseline values for the mean number of micturitions, volume voided in each micturition, nocturia episodes, urgency and urgency incontinence episodes were 15.3±0.34, 128±3.88mL, 3.96±1.67, 5.72±1.35 and 4.22±0.69, respectively. After treatment, values for these parameters were 11.7±0.29, 164.7±2.9mL, 2.25±0.6, 3.38±0.71, 2.31±0.49 respectively. Quality of life score, symptom bother score, VAS for treatment satisfaction score, PPBC score after treatment were 66.1±0.85, 43.7±0.77, 4.78±0.14, 4.78±0.14, respectively. There were no significant differences between two groups on any parameter. However, mirabegron showed better tolerability than solifenacin, particularly after 6 months. Conclusion Mirabegron is safe, effective and tolerable in the long-term treatment of females with OAB symptoms after surgery for stress urinary incontinence.

Meta-Analysis of the Efficacy and Safety of Mirabegron Add-On Therapy to Solifenacin for Overactive Bladder / 대한배뇨장애요실금학회지

PURPOSE: We performed a meta-analysis to evaluate the efficacy and safety of mirabegron add-on therapy to solifenacin for patients with overactive bladder (OAB). METHODS: We conducted a systematic literature review to identify all randomized, double-blind, controlled trials (RCTs) of this combination (mirabegron and solifenacin) for OAB. Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched. A manual search was also performed to investigate relevant references from the retrieved studies. RESULTS: Four publications describing 5 RCTs that compared combination therapy with solifenacin, including a total of 3,309 patients, were analyzed. The mean number of micturitions per 24 hours (mean difference [MD], -0.45; 95% confidence interval [CI], -0.65 to -0.26; P < 0.00001), number of episodes of incontinence per 24 hours (MD, -0.71; 95% CI, -0.14 to -0.02; P=0.04), volume voided per micturition, and number of urgency episodes per 24 hours demonstrated that combination therapy was more effective than solifenacin therapy alone. Safety assessments, including common treatment-emergent adverse events (odds ratio, 1.09; 95% CI, 0.95–1.27; P=0.23) and discontinuations due to adverse events (P=0.30), demonstrated that the combination therapy was well tolerated. CONCLUSIONS: This meta-analysis suggests that mirabegron therapy as an add-on to solifenacin provides a satisfactory therapeutic effect for OAB symptoms with a low occurrence of side effects.

Optimization of Mirabegron Sustained-release Tablets by Central Composite Design-response Surface Meth-od / 中国药房

OBJECTIVE:To optimize the formulation of Mirabegron sustained-release tablets. METHODS:Using polyethylene oxide(PEO)and hydroxypropylmethyl cellulose(HPMC K4M)as the sustained release matrix,Mirabegron sustained-release tab-lets were prepared by powder direct compression technology. Using 1,3,5,7 h accumulative release rate as indexes,the amounts of PEO,HPMC K4M and OPADRY? were optimized by composite design-response surface method,and then validated. Accumula-tive release rates of sustained-release tablet and original tablet (MyrbetriqTM) were compared in different pH mediums (water,pH 1.0 simulated gastric fluid,pH 4.5 acetate buffer solution,pH 6.8 phosphate buffer solution) at different rotation rates (100,50 r/min),and similiar factor f2 was calculated to fit drug release model of sustained-release tablet. RESULTS:In the optimized firmu-lation each Mirabegron sustained-release tablet contained mirabegron 25 mg,PEO 108.02 mg,HPMC K4M 21.69 mg,OPADRY? 2.27%. Relative error of accumulative release rates at 1,3,5,7 h to predicted value were 4.78%,3.48%,0.69% and -1.41%, respectively. f2 of release curves of sustained-release tablet and original tablet were higher than 65 in different pH medium at differ-ent rotation rates. The drug release of sustained-release tablet was fitted to zero-order release equation. CONCLUSIONS:Mirabe-gron sustained-release tablet by optimized technology is similar to original tablet in drug release behavior.

Pharmacokinetics of mirabegron sustained-release tablets in beagle dogs / 中国药学杂志

OBJECTIVE: To establish a simple, sensitive method of liquid chromatographic-tandem mass spectrometric (LC-MS/MS) for determination of mirabegron in dog plasma, and to evaluate the pharmacokinetics for single dose of different formulations of mirabegron sustained-release tablets in dogs. METHODS: The analyte mirabegron and internal standards (IS) tolbutamide were separated on a BEH C18 column (2.1 mm×50 mm, 1.7 μm) with mobile phase of 0.1% formic acid water solution-0.1% formic acid methyl cyanides solution using a gradient elution mode at a flow rate of 450 μL·min-1. In accordance with randomized two-period self crossover study, eight dogs were given single oral dose of the test preparation and reference preparation, then the concentration of mirabegron in plasma was determined, the pharmacokinetic parameters were calculated and the difference of the two preparations were evaluated. RESULTS: The linear range of mirabegron in Beagle dogs plasma was 1-1000 ng·mL-1. The accuracy and the precisions of intra-day and inter-day also were qualified. After a single dose administration of the test preparation and reference preparation, the pharmacokinetic parameters were as follow: t1/2 were (7.14±1.59) vs (7.13±1.78) h, pmax were (144.4±77.5) vs (130.3±39.2) ng·mL-1, tmax were (3.72±1.87) vs (4.64±1.55)h, AUC0→8 were (1021±439) vs (989±299)ng·h·mL-1, AUC0→∞ were (1043±441) vs (1010±301)ng·h·mL-1. CONCLUSION: The LC-MS/MS method is suitable for pharmacokinetic study of mirabegron. Moreover, there is no significant difference in the pharmacokinetic profiles between the two preparations of mirabegron.