A Phase 1, open-label, crossover study evaluating the effect of a single dose of sodium zirconium cyclosilicate on the pharmacokinetics of tacrolimus and cyclosporin.

Background: Sodium zirconium cyclosilicate (SZC) is an oral, highly selective potassium binder approved for the treatment of hyperkalaemia in adults. SZC may change the absorption of co-administered drugs that exhibit pH-dependent bioavailability. This study evaluated whether the pharmacokinetic (PK) profiles of tacrolimus and cyclosporin were altered by concomitant SZC administration in healthy participants. Methods: This was an open-label, randomised sequence, two-cohort crossover, single-centre study. Healthy adults were assigned to one of two cohorts: Cohort 1 (tacrolimus) received a single dose of tacrolimus 5 mg and tacrolimus 5 mg + SZC 15 g in a random order; Cohort 2 (cyclosporin) received a single dose of cyclosporin 100 mg and cyclosporin 100 mg + SZC 15 g in a random order. Primary PK endpoints were maximum observed blood concentration (Cmax) and area under the concentration-time curve (AUC) from time zero to infinity (AUCinf). Differences in mean Cmax and AUCinf were analysed using a mixed effects model. Results: Thirty participants in Cohort 1 and 29 in Cohort 2 completed the study. Tacrolimus exposure was lower with tacrolimus + SZC versus tacrolimus alone: Cmax geometric mean ratio (GMR) 71.10% [90% confidence interval (CI) 65.44-77.24], AUCinf 62.91% (55.64-71.13). Cyclosporin exposure was similar with cyclosporin + SZC compared with cyclosporin alone: Cmax GMR 102.9% (90% CI 96.11-110.10), AUCinf 97.23% (92.93-101.70). Conclusions: Tacrolimus exposure was lower when co-administered with SZC 15 g and should be administered ≥2 h before or after SZC. The PK profile of cyclosporin was not affected by SZC co-administration.

The use of mono- and combination drug therapy in men and women with lower urinary tract symptoms (LUTS) in the UK: a retrospective observational study.

BACKGROUND: Combination drug therapy for lower urinary tract symptoms (LUTS) is beneficial to selected patients and recommended by guidelines. Patterns of real-world LUTS drug use, especially combination drug therapy, have not been studied extensively. Moreover, further understanding of the recent landscape is required following the introduction of the beta-3-adrenoceptor agonist mirabegron in the UK in 2013 for overactive bladder (OAB). The objective was to describe mono- and combination drug therapy use for LUTS in patients in UK clinical practice. METHODS: This was a retrospective, descriptive, observational database study using UK Clinical Practice Research Datalink GOLD and linked databases. Men and women ≥ 18 years with a first prescription for any LUTS drug from 2014 to 2016 with ≥ 12 months continuous enrollment pre- and post-index date were included. Primary endpoints were mono- or combination drug therapy use for LUTS in male and female cohorts. Secondary endpoints were description of treatment prescribed, treatment persistence and patient demographics. Data were analyzed descriptively. Sub-cohorts were defined by drugs prescribed at index date. RESULTS: 79,472 patients (61.3% male) were included, based on index treatments. Of all men, 82.5% received any benign prostatic obstruction (BPO) drug, 25.4% any OAB drug, and 7.9% any BPO drug plus any OAB drug. As either mono- or combination drug therapy, 77.1% received an alpha-blocker, 18.9% a 5-alpha reductase inhibitor, 23.9% an antimuscarinic agent, and 2.1% mirabegron. Of all women, 94.5% received any OAB drug, 6.0% duloxetine, and 0.5% any OAB drug plus duloxetine. As either mono- or combination drug therapy, 87.7% received an antimuscarinic, and 9.7% mirabegron. In men or women receiving OAB treatment, approximately 2.5% received combination drug therapy with an antimuscarinic agent and mirabegron. For OAB drug monotherapies, mirabegron had the highest persistence in both male and female cohorts. CONCLUSIONS: This study provides a better understanding of the recent landscape of LUTS drug use in UK clinical practice. It highlights potential undertreatment of storage symptoms in men with LUTS and the low use of combination OAB treatments.

Anticholinergic Burden and Associated Healthcare Resource Utilization in Older Adults with Overactive Bladder.

BACKGROUND: Bladder anticholinergics are the most widely used drugs to treat overactive bladder (OAB) but can contribute to cumulative anticholinergic burden, which may be associated with adverse outcomes. OBJECTIVE: This study aimed to evaluate the association between cumulative anticholinergic burden and healthcare resource utilization (HRU) and costs in older adults with OAB. MATERIALS AND METHODS: This was a retrospective, observational study that used data from the UK Clinical Practice Research Datalink (CPRD) GOLD database. Participants were aged ≥ 65 years with ≥ 3 years of continuous enrolment before and ≥ 2 years after the index date (date of OAB diagnosis or first prescription for any OAB drug between 1 April 2007 and 31 December 2015). The primary endpoint was the association between cumulative anticholinergic burden (assessed using the Anticholinergic Cognitive Burden [ACB] scale during the 3-year pre-index period) and HRU (GP consultations, specialist referrals, urological tests, hospital admissions) over the 2-year post-index period. RESULTS: Data from 23,561 adults were included in the analysis. Mean (SD) ACB scores in the pre- and post-index periods were 1.0 (1.1) and 2.4 (1.7), respectively; urological drugs contributed most (58.8%) to the latter. For the primary endpoint, higher pre-index ACB scores were associated with higher post-index HRU and costs. Mean (SD) ACB scores in the post-index period were 1.2 (1.3) and 2.5 (1.7) in those treated with mirabegron (beta-3 agonist) or bladder anticholinergics, respectively. LIMITATIONS: The generalizability of the results outside the UK is unclear. CONCLUSIONS: In older adults with OAB, higher anticholinergic burden before initiating OAB drugs is associated with higher HRU and costs. When making treatment decisions in older adults, consideration should be given to assessing the existing anticholinergic burden and using OAB treatments that do not add to this burden.

Mirabegron Vs Placebo Add-on Therapy in Men With Overactive Bladder Symptoms Receiving Tamsulosin for Underlying Benign Prostatic Hyperplasia: A Safety Analysis From the Randomized, Phase 4 PLUS Study.

OBJECTIVE: To analyze the safety of mirabegron add-on therapy in men with overactive bladder symptoms concurrently receiving tamsulosin for lower urinary tract symptoms associated with benign prostatic hyperplasia. METHODS: The Phase 4 PLUS study comprised a 4-week run-in period (tamsulosin [0.4 mg]) and a 12-week randomized treatment period (add-on treatment: mirabegron [25 mg] or placebo). Doses were increased to mirabegron 50 mg or matched placebo after 4 weeks. Safety assessments: treatment-emergent adverse events (TEAEs), vital signs, 12-lead electrocardiograms, and changes in postvoid residual volume and maximum urinary flow (Qmax). RESULTS: The safety analysis set included 352 tamsulosin plus mirabegron (TAM + MIRA) and 354 tamsulosin plus placebo (TAM + PL) patients. The frequency of overall TEAEs was higher with TAM + PL, although a higher incidence of drug-related TEAEs was observed with TAM + MIRA. Most TEAEs were mild or moderate in severity. Drug-related serious TEAEs were reported for 3 patients (2 TAM + MIRA patients: acute myocardial infarction with cerebral infarction and angina pectoris, 1 TAM + PL patient: lacunar stroke). Hypertension, headache, and nasopharyngitis were the most common TEAEs. Special interest TEAEs were infrequently reported. The most common was urinary retention and 2 TAM + MIRA patients required catheterization (neither led to discontinuation). No major changes in blood pressure or pulse rate were noted and similar electrocardiogram parameters were observed for both groups. Changes in mean postvoid residual volume and Qmax were not clinically meaningful. CONCLUSION: No unexpected safety concerns were noted in men receiving tamsulosin for lower urinary tract symptoms associated with benign prostatic hyperplasia who subsequently received mirabegron add-on therapy.

Efficacy and Safety of Mirabegron versus Placebo Add-On Therapy in Men with Overactive Bladder Symptoms Receiving Tamsulosin for Underlying Benign Prostatic Hyperplasia: A Randomized, Phase 4 Study (PLUS).

PURPOSE: PLUS investigated the efficacy and safety of mirabegron add-on therapy in men with overactive bladder symptoms receiving tamsulosin for underlying lower urinary tract symptoms attributable to benign prostatic hyperplasia. MATERIALS AND METHODS: In this phase 4 study a 4-week 0.4 mg tamsulosin run-in period was followed by a 12-week, randomized, double-blind, treatment period in which patients initially received 25 mg mirabegron or placebo add-on therapy. At 4 weeks doses were titrated to 50 mg mirabegron or placebo equivalent. Efficacy end points were changes from baseline to end of treatment in mean number of micturitions per day (primary), mean volume voided per micturition, number of urgency episodes per day, total urgency and frequency score, and total International Prostate Symptom Score (secondary). Safety assessments included treatment emergent adverse events, and post-void residual volume, and maximum urinary flow measurements. RESULTS: Of the 676 men most were 65 years old or older (380, 56.2%). Tamsulosin plus mirabegron was statistically superior to tamsulosin plus placebo in reducing the mean number of micturitions per day (-2.00 vs -1.62; adjusted difference -0.39; 95% CI -0.76, -0.02). Statistically superior results were noted for tamsulosin plus mirabegron in mean volume voided per micturition, urgency episodes per day, and total urgency and frequency score (not International Prostate Symptom Score). Higher overall treatment emergent adverse event rates were observed with tamsulosin plus placebo, although higher rates of drug related treatment emergent adverse events were noted with tamsulosin plus mirabegron. Urinary retention rates were higher in the tamsulosin plus mirabegron group. Post-void residual volume and maximum urinary flow results were not clinically meaningful. CONCLUSIONS: The results of PLUS underscore the utility of mirabegron add-on therapy to treat men with overactive bladder symptoms receiving tamsulosin for benign prostatic hyperplasia.

Safety and Efficacy of Mirabegron: Analysis of a Large Integrated Clinical Trial Database of Patients with Overactive Bladder Receiving Mirabegron, Antimuscarinics, or Placebo.

BACKGROUND: Mirabegron, a ß3-adrenoreceptor agonist, is an alternative drug to antimuscarinics for overactive bladder (OAB) symptoms. OBJECTIVE: To summarise safety and efficacy reporting of mirabegron treatment for OAB symptoms. DESIGN, SETTING, AND PARTICIPANTS: Pooled data analysed from 10 phase 2-4, double-blind, 12-wk mirabegron monotherapy studies in adults with OAB who had received one or more doses of study drug. INTERVENTION: Mirabegron: 25 and 50mg; antimuscarinics: solifenacin (2.5, 5, and 10mg) and tolterodine extended release (4mg). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline OAB-related characteristics, intrinsic and extrinsic factors, and analyses by age (<65 vs ≥65yr and <75 vs ≥75yr) and sex were assessed. Solifenacin 2.5 and 10mg groups were not included in the efficacy analyses (small patient numbers). Safety was evaluated using the proportion of treatment-emergent adverse events. Efficacy variables were derived from bladder diaries (baseline and week 12). RESULTS AND LIMITATIONS: Baseline hypertension and diabetes were more frequent across treatment groups in the older versus younger age groups and in men versus women. Within sexes, frequencies were similar between treatment groups. Some differences were observed in baseline characteristics, including type of incontinence and medical history between sexes. No previously unreported safety concerns were identified. Improvements in efficacy (mean number of incontinence episodes/24h, micturitions/24h, urgency episodes/24h, volume voided/micturition, and nocturia episodes) versus placebo were observed in all treatment groups. Significant treatment-by-subgroup interactions included change from baseline in the mean number of incontinence episodes/24h by age (<65 vs ≥65yr), nocturia by age (<65 vs ≥65yr and <75 vs ≥75yr), and urgency episodes by previous OAB medication. CONCLUSIONS: Data from this integrated database of 10 mirabegron studies reaffirm the safety and efficacy profiles of mirabegron, solifenacin, and tolterodine in adults of different age groups and sexes. PATIENT SUMMARY: Overactive bladder is a complex of symptoms including a compelling desire to pass urine that leads to increased frequency, which may lead to a degree of incontinence if you do not reach the toilet in time and may wake you from sleep. We pooled data from 10 different studies of mirabegron in patients with overactive bladder symptoms, and looked at the effect in the total number of patients who received the treatment, as well as in different age groups and between men and women. No new safety concerns were identified, and mirabegron improved the symptoms of overactive bladder.

Quality of life in patients aged 65 years and older with overactive bladder treated with mirabegron across eight European countries: Secondary analysis of BELIEVE.

OBJECTIVES: To describe quality of life outcomes in patients with overactive bladder aged ≥65 years receiving mirabegron, a ß3-adrenoreceptor agonist (BELIEVE). METHODS: BELIEVE was a European, prospective, non-interventional, real-world study of 848 patients with overactive bladder prescribed mirabegron in clinical practice. Overactive bladder questionnaire subscales were prespecified primary end-points, analyzed in the full analysis set (patients completing the questionnaire at baseline and ≥1 follow-up visit) and per protocol set (patients still taking mirabegron at 10-12 months) using accepted standards for minimally important differences (10 points). RESULTS: Nearly half of the patients in the full analysis set (380/796 [47.7%]) and per protocol set (224/452 [49.6%]) were aged ≥65 years. Similar proportions of patients aged ≥65 years (224/407; 55.0%) and <65 years (228/441; 51.7%) were taking mirabegron at 10-12 months. Mean symptom bother scores improved from baseline to month 10-12 in older patients (full analysis set 52.4 to 32.9; per protocol set 51.6 to 30.4) and younger patients (full analysis set 52.2 to 27.4; per protocol set 47.8 to 23.7). Proportions of older/younger patients with improvement in symptom bother were similar (full analysis set 52.1%/52.9%; per protocol set 70.1%/72.4%, respectively). Mean total quality of life scores improved in older patients (full analysis set 60.7-75.9; per protocol set 61.1-77.5) and younger patients (full analysis set 54.9 to 77.6; per protocol set 56.8 to 80.1). No unexpected safety issues were observed. CONCLUSIONS: Patients aged ≥65 years receiving mirabegron in clinical practice reported clinically meaningful improvements in quality of life.

Drug utilization patterns and healthcare resource use and costs in patients with neurogenic bladder in the United Kingdom: A retrospective primary care database study.

AIM: To characterize patients with neurogenic bladder (NGB), their treatment patterns, healthcare resource utilization, and associated costs based on records from a primary care database in the United Kingdom. METHODS: This was a retrospective, descriptive, observational study of anonymized data from the Clinical Practice Research Datalink and Hospital Episode Statistics databases (selection period, 1 January 2004 to 31 December 2016). Adults with a definitive or probable diagnosis of NGB and ≥1 referral to a urologist were included. RESULTS: The study cohort included 3913 patients with definitive (n = 363) or probable (n = 3550) NGB. Patients had a mean of 8.6 (standard deviation [SD], 7.6) comorbidities, and mean Anticholinergic Cognitive Burden Scale score of 6.6 (SD, 5.9). During 12 months' follow-up, urinary tract infection (UTI) and urinary incontinence were the most common complications. Most patients (92.2%) received ≥1 prescription for an antimuscarinic agent or mirabegron, and 53.9% of patients received prescriptions for UTI-specific antibiotics. The mean number of visits to a general practitioner for any cause was 67.7 (SD, 42.6) per individual. Almost half (46.7%) of the study cohort visited a specialist during the 12-month follow-up period, and 11.0% had ≥1 hospital admission. Total mean per patient costs for healthcare resource utilization was £2395. CONCLUSIONS: The burden of illness, healthcare resource needs, and associated costs among patients with NGB are considerable. Drug prescribing patterns are consistent with the symptoms and complications of NGB, although increased awareness of drugs with anticholinergic activity among prescribers may help to reduce the cumulative anticholinergic burden in this vulnerable population.

The efficacy of mirabegron in the treatment of urgency and the potential utility of combination therapy.

Urgency is the prevalent and most bothersome symptom of overactive bladder (OAB) and the treatment of urgency is the primary objective in the management of OAB. Urgency has a major impact on other symptoms of OAB and culminates in an increased frequency of micturition and reduced volume voided, which may contribute to shorter intervals between the need to void. Antimuscarinic agents and mirabegron, a ß3-adrenoceptor agonist, constitute the main oral pharmacotherapeutic options for the treatment of urgency and other OAB symptoms. The reduction of urgency and other OAB symptoms significantly improve health-related quality of life. This review will explore the distinct mechanisms of action and effects of antimuscarinic agents and mirabegron, in relation to their effect on the pathophysiology of urgency. The review will also provide an overview of the various validated measurements of urgency and the numerous clinical trials regarding antimuscarinic agent monotherapy, mirabegron monotherapy, or combination treatment with mirabegron added on to the antimuscarinic agent solifenacin. A narrative review of the literature relating to pathophysiology of urgency, the validated measurements of urgency, and clinical trials relating to the pharmacological treatment of urgency. Antimuscarinic agent monotherapy, mirabegron monotherapy, or combination treatment with mirabegron added on to the antimuscarinic agent solifenacin statistically significantly reduce the symptoms of urgency compared with placebo. Combination therapy with mirabegron added on to solifenacin also statistically significantly reduces the symptoms of severe urgency compared with antimuscarinic agent monotherapy. A critique of the clinical benefits of combination therapy is also provided. Combination therapy provides an alternative treatment in patients with OAB that includes urgency who respond poorly to first-line monotherapy and who may otherwise often move on to more invasive treatments.

Mirabegron improves quality-of-life, treatment satisfaction, and persistence in patients with overactive bladder: a multi-center, non-interventional, real-world, 12-month study.

OBJECTIVE: Observational studies can provide evidence about patient outcomes in routine clinical practice. This prospective, non-interventional study (BELIEVE) is the largest real-world European study to date to assess quality-of-life, treatment satisfaction, resource utilization, and persistence in patients with overactive bladder (OAB) who were prescribed mirabegron as part of routine clinical practice. METHODS: The primary objective was to evaluate change from baseline in quality-of-life based on overactive bladder questionnaire (OAB-q) sub-scales. Secondary objectives included evaluation of treatment persistence, patient satisfaction, healthcare resource utilization and adverse events (AEs). Follow-up was for 12 months with visit windows at 2-4 and 10-12 months. Median change from baseline in total OAB-q and its sub-scales (Health-related quality-of-life [HRQoL] and symptom bother scale) were assessed. RESULTS: Overall, 862 patients were enrolled from eight European countries. In the Full Analysis Set (FAS), 73.7% were female, mean age was 61.2 years; 47.7% ≥65 years. At baseline, 41.3% had switched from other OAB treatments, 42.2% were treatment naïve, 10.1% were lapsed, and 6.4% were on combination treatment. Symptom bother and HRQoL total scores improved from baseline to 2-4 and 10-12 months. There was a notable improvement in dry rate, increasing from 34.9% at baseline to 43.7% at 10-12 months in the FAS, and a reduction in pad use. Persistence was high, with 53.8% of FAS patients remaining on mirabegron at 10-12 months. Overall, no unexpected safety issues were observed and AEs were consistent with the known safety profile of mirabegron. CONCLUSION: Patients receiving mirabegron in a real-world setting reported meaningful improvements in QoL and health status, with a persistence rate of 53.8% at 12 months for the FAS. No unexpected safety issues were observed, and AEs were consistent with the known safety profile of mirabegron.

Treating Overactive Bladder in Older Patients with a Combination of Mirabegron and Solifenacin: A Prespecified Analysis from the BESIDE Study.

BACKGROUND: The BESIDE study demonstrated that combination therapy (mirabegron and solifenacin 5mg) improved overactive bladder symptoms versus solifenacin 5mg or 10mg, and was well tolerated. OBJECTIVE: To ensure efficacy and safety is maintained in older patients (>65 yr), who usually experience greater symptom severity and comorbidities, a prespecified subanalysis stratified by age group was conducted. DESIGN, SETTING, AND PARTICIPANTS: Patients remaining incontinent (≥1 episode during 3-d diary) following 4-wk single-blind daily solifenacin 5mg were randomized 1:1:1 to a daily double-blind combination (solifenacin 5mg and mirabegron 25mg, increased to 50mg at wk 4), solifenacin 5mg or 10mg for 12 wk. Four cohorts stratified by age (<65 yr, ≥65 yr and < 75 yr, ≥75 yr) were investigated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Efficacy assessments: change from baseline to end of treatment in average daily incontinence (primary) and micturition frequency (key secondary), number of incontinence episodes during the 3-d diary (key secondary), and change from baseline in average daily urgency and urgency incontinence episodes. Safety included treatment-emergent adverse events and vital signs. RESULTS AND LIMITATIONS: Full analysis set included 2110 patients: 30.9% aged ≥65 yr and 8.9% aged ≥75 yr. At the end of treatment, daily, and 3-d incontinence daily micturitions, urgency, and urgency incontinence, were improved in each treatment group and age group; the largest reductions were observed with combination in each age cohort. There were no notable differences in vital signs or the incidence of treatment-emergent adverse events between treatment and age groups, with the exception of dry mouth, which was highest with solifenacin 10mg. CONCLUSIONS: Efficacy and safety in the overall population is maintained in older (≥65 yr) and elderly (≥75 yr) patients treated with a combination of solifenacin and mirabegron, or solifenacin monotherapy; irrespective of age, combination was associated with the greatest improvement in overactive bladder symptoms. PATIENT SUMMARY: This study investigated the effectiveness and safety of a combination of two different treatments (mirabegron 50mg and solifenacin 5mg) or solifenacin (5mg or 10mg) alone in patients aged <65 yr or ≥65 yr, and <75 yr or ≥75 yr with overactive bladder. Symptoms of overactive bladder, such as the urgent need to visit the toilet, incontinence, and frequent urination, were improved with all treatments regardless of the patient's age, but combination treatment demonstrated the greatest benefit, and was well tolerated.

Prevalence of metabolic syndrome and its components among men with and without clinical benign prostatic hyperplasia: a large, cross-sectional, UK epidemiological study.

OBJECTIVES: To compare the prevalence of metabolic syndrome and the components of metabolic syndrome in men aged ≥50 years with and without clinical benign prostatic hyperplasia (BPH). SUBJECTS AND METHODS: This was a cross-sectional study using the UK Clinical Practice Research Datalink (CPRD). Men were selected from the CPRD who were aged ≥50 years and still registered as of 31 December 2011. Cohort 1 included men with clinical BPH, and cohort 2 men without clinical BPH who were matched 1:1 to those in cohort 1 by general practice, year of birth and previous years of available history (1-<2, 2-<3, 3-<4, ≥4 years of available history). The prevalence of metabolic syndrome and its components (for men alive and still registered in the CRPD as of 31 December 2011) was calculated using all available history (lifetime prevalence) and medical history from 2010 and 2011 (current prevalence). Crude odds ratios and 95% confidence intervals for the occurrence of metabolic syndrome and the occurrence of the components of metabolic syndrome were calculated by comparing men with and without BPH. RESULTS: A total of 26.5% of men with clinical BPH had metabolic syndrome compared with 20.9% of matched controls without clinical BPH (absolute difference 5.6%; P < 0.001); men with clinical BPH were therefore significantly more likely to have metabolic syndrome than matched controls without clinical BPH. Significantly greater proportions of men with clinical BPH also had each component of metabolic syndrome compared with matched controls without clinical BPH. The presence of clinical BPH was associated with a 37% increased odds of having metabolic syndrome (for both lifetime prevalence and current prevalence) compared with matched controls without clinical BPH. CONCLUSIONS: There is a significant cross-sectional association between clinical BPH and metabolic syndrome in the UK primary care population.