Oral Controlled Absorption System Research Articles

Factors Associated With Nocturia-Related Quality of Life in Men With Lower Urinary Tract Symptoms and Treated With Tamsulosin Oral Controlled Absorption System in a Non-Interventional Study.

Nocturia impairs quality of life (QoL). We have performed a non-interventional study in which men with lower urinary tract symptoms (LUTS) were treated for at least 3 months with tamsulosin oral controlled absorption system (0.4 mg q.d.). Other than observing efficacy and tolerability of this drug formulation, the study was designed to explore the relative roles of number of nocturia episodes and of non-urological causes of nocturia on nocturia-related QoL at baseline and treatment-associated changes thereof. The study enrolled 5775 men seeking treatment of their LUTS. Tamsulosin improved LUTS, e.g. International Prostate Symptom Score from 19.5 ± 5.9 to 10.1 ± 4.9 (means ± SD). This was associated by clinically meaningful improvements in the Nocturia QoL score (from 45 ± 19 to 73 ± 17 points) and other QoL scores. Number of nocturnal voids was the key driver of all QoL scores at baseline; change of number of nocturia episodes that of improvement of all QoL scores upon treatment. In contrast, non-urological causes of nocturia such as heart failure, diabetes, sleep apnea, fluid or alcohol intake or use of diuretics or hypnotics had only small if any effects on baseline QoL or treatment-associated improvements thereof. The observed effects of non-urological causes on QoL apparently were largely driven by their effect on number of nocturnal voids. These data further support the idea that improvement of nocturia may be an important treatment goal in male LUTS.

Safety of Tamsulosin: A Systematic Review of Randomized Trials with a Focus on Women and Children

Although tamsulosin is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH), it has also been assessed in clinical studies for other conditions/symptoms and in other populations such as women and children. In this systematic review of randomized studies, the overall safety of tamsulosin was assessed, focusing on these understudied populations. Literature searches were conducted using Embase, Medline, and PubMed (inception-December 2015). A study was included if patients were randomized to receive treatment with any dose of tamsulosin capsules, tablets, or an oral controlled absorption system and numerical safety results were reported. Overall, 160 articles involving 46,072 participants met the inclusion criteria. Of these, four studies included women only and three included children. The mean [standard deviation (SD)] age ranged from 7.3 (4.2) to 76.8 (7.1) years. The studies (n; %) evaluated healthy subjects (18; 11%) or patients with lower urinary tract symptoms/BPH (90; 56%), ureteral stones/renal colic (42; 26%), prostatitis (4; 3%), or other conditions (6; 4%). Patients discontinued tamsulosin primarily because of adverse events (AEs) or insufficient response. AEs in women and children were abdominal pain, asthenia, constipation, dizziness, dry mouth, drowsiness, dyspepsia, headache, incontinence, nasal congestion, nausea, orthostatic hypotension, and somnolence. Due to heterogeneity across studies, statistical analysis could not be conducted. No unexpected AEs were observed in an all-comers population treated with tamsulosin for various conditions/symptoms. The overall safety profile in women and children seemed to be generally consistent with the profile in men, the indicated population.

Benign prostatic hyperplasia and lower urinary tract symptoms. A review of current evidence

ContextThe treatment of benign prostatic hyperplasia (BPH) is changing due to a greater understanding of the disease and the development of the functional concept of lower urinary tract symptoms (LUTS). ObjectivesTo describe the current state of BPH and the diagnosis and treatment of LUTS. Acquisition of evidenceWe summarize the issues presented and debated by a group of expert urologists during the First UROVI Congress, sponsored by the Spanish Urological Association. Summary of the evidenceLUTS encompasses filling, voiding and postvoiding symptoms that affect patients’ quality of life. The aetiological diagnosis is an important element in starting the most ideal treatment. For this reason, new alternative therapies (both pharmacological and surgical) are needed to help individually address the symptoms in the various patient profiles. There is now a new combination of drugs (6mg of solifenacin and 0.4mg of the tamsulosin oral controlled absorption system) for treating moderate to severe filling symptoms and emptying symptoms associated with BPH in patients who do not respond to monotherapy. Furthermore, new surgical techniques that are increasingly less invasive help provide surgical options for older patients and those with high comorbidity. ConclusionsThe availability of drugs that can act on the various LUTS helps integrate the pathophysiological paradigm into the functional one, providing more appropriate treatment for our patients.

Efficacy and safety of tamsulosin oral-controlled absorption system, solifenacin, and combined therapy for the management of ureteric stent-related symptoms

ObjectivesTo evaluate the efficacy of solifenacin, tamsulosin oral-controlled absorption system (OCAS), and the combination of both drugs on JJ stent-related symptoms using the validated Arabic version of the ureteric stent symptom questionnaire (USSQ). Patients and methodsIn all, 260 patients who had undergone JJ stenting of the ureter for different endoscopic urological procedures were postoperatively randomly assigned into four equal groups. Patients in Group I received no treatment and served as the control group, Group II patients received tamsulosin OCAS 0.4mg daily, Group III patients received solifenacin 5mg daily, and Group IV patients received a combination of both drugs. Before stent removal, all patients completed the Arabic version of the USSQ. ResultsIn all, 234 patients completed the study, comprised of 56 in Group I, 59 in Group II, 58 in Group III, and 61 in Group IV. Baseline characteristics and indications for JJ stenting were comparable in the four groups. There were highly significant differences in all items of the USSQ between the treatment groups and the controls, while Group II and III were comparable. The USSQ score was significantly lower in Group IV vs Groups II and III. Crossing of the distal curl of the stent to the midline had a significant positive correlation with the severity of the urinary symptoms, body pain, general health, and work performance in the medicated groups. ConclusionsCombined therapy with tamsulosin OCAS 0.4mg daily and solifenacin 5mg daily is a safe and well-tolerated management for stent-related symptoms. However, stent position remains a significant factor affecting response to medical therapy and patients’ health-related quality of life.

Hiperplasia prostática benigna y síntomas del tracto urinario inferior. Revisión de las evidencias actuales

ContextThe treatment of benign prostatic hyperplasia (BPH) is changing due to a greater understanding of the disease and the development of the functional concept of lower urinary tract symptoms (LUTS). ObjectivesTo describe the current state of BPH and the diagnosis and treatment of LUTS. Acquisition of evidenceWe summarise the issues presented and debated by a group of expert urologists during the First UROVI Congress, sponsored by the Spanish Urological Association. Summary of the evidenceLUTS encompasses filling, voiding and postvoiding symptoms that affect patients’ quality of life. The aetiological diagnosis is an important element in starting the most ideal treatment. For this reason, new alternative therapies (both pharmacological and surgical) are needed to help individually address the symptoms in the various patient profiles. There is now a new combination of drugs (6mg of solifenacin and 0.4mg of the tamsulosin oral controlled absorption system) for treating moderate to severe filling symptoms and emptying symptoms associated with BPH in patients who do not respond to monotherapy. Furthermore, new surgical techniques that are increasingly less invasive help provide surgical options for older patients and those with high comorbidity. ConclusionsThe availability of drugs that can act on the various LUTS helps integrate the pathophysiological paradigm into the functional one, providing more appropriate treatment for our patients.

Cost-effectiveness of a fixed-dose combination of solifenacin and oral controlled adsorption system formulation of tamsulosin in men with lower urinary tract symptoms associated with benign prostatic hyperplasia.

BackgroundStorage symptoms, associated with benign prostatic hyperplasia (BPH), often co-exist with voiding symptoms in men with lower urinary tract symptoms (LUTS). Storage symptoms are likely to be most bothersome, and may not be adequately resolved by treatment with α-blocker or antimuscarinic monotherapy. A recent randomised controlled phase 3 trial (NEPTUNE) demonstrated that a fixed-dose combination (FDC) of solifenacin 6 mg plus an oral controlled absorption system (OCAS™) formulation of tamsulosin (TOCAS, 0.4 mg) improved storage symptoms, as well as quality of life, compared with TOCAS alone in men with moderate-to-severe storage symptoms and voiding symptoms. This analysis aimed to assess the cost-effectiveness of a FDC tablet of solifenacin 6 mg plus TOCAS relative to tolterodine plus tamsulosin given concomitantly, from the perspective of the UK National Health Service (NHS).MethodsA Markov model was developed for men aged ≥45 years with LUTS/BPH who have moderate-to-severe storage symptoms and voiding symptoms. The model calculated cost-effectiveness over an analytical time horizon of 1 year and estimated total treatment costs, quality adjusted life years (QALYs) and incremental cost-effectiveness ratio.ResultsThe FDC tablet of solifenacin 6 mg plus TOCAS was associated with lower total annual costs (£860 versus £959) and increased QALYs (0.839 versus 0.836), and was therefore dominant compared with tolterodine plus tamsulosin. Time horizon, discontinuation or withdrawal rates, drug cost and utility values were the main drivers of cost-effectiveness. The probability that the FDC tablet of solifenacin 6 mg plus TOCAS is cost-effective was 100% versus tolterodine plus tamsulosin, at a willingness-to-pay threshold of £20,000/QALY gained.ConclusionsThe FDC tablet of solifenacin 6 mg plus TOCAS provides important clinical benefits and is a cost-effective treatment strategy in the UK NHS compared with tolterodine plus tamsulosin for men with both storage and voiding LUTS/BPH.Electronic supplementary materialThe online version of this article (doi:10.1186/s12894-015-0031-8) contains supplementary material, which is available to authorized users.

Solifenacin/tamsulosin fixed-dose combination therapy to treat lower urinary tract symptoms in patients with benign prostatic hyperplasia.

Treatment of male lower urinary tract symptoms (LUTS) has traditionally focused on the management of benign prostatic obstruction, but the contribution of bladder dysfunction has been recently recognized. Therefore, it is well understood that LUTS have multifactorial etiology and often occur in clusters and not in isolation. Voiding LUTS are highly prevalent in men, but storage LUTS have been proved to be more bothersome. α1-Blockers are the most widely used pharmacologic agents for the treatment of symptoms relating to benign prostatic enlargement due to benign prostatic hyperplasia (BPH), while antimuscarinics are the drug class of choice for overactive bladder symptoms. A combination of the two drug classes would be a reasonable approach to treat men with both storage and voiding symptoms, and several short-term studies have proved the efficacy and safety of different combinations with an α1-blocker and an antimuscarinic. Following previous studies on the separate administration of solifenacin and tamsulosin, a fixed-dose combination tablet of tamsulosin oral controlled absorption system (OCAS) 0.4 mg and solifenacin succinate 6 mg has been recently introduced, and the current review evaluates the available data on the use of this fixed-dose combination in the treatment of LUTS in men with BPH.

Efficacy and safety of solifenacin plus tamsulosin oral controlled absorption system in men with lower urinary tract symptoms: a meta-analysis.

We performed a meta-analysis to compare treatment with a combination of solifenacin plus tamsulosin oral controlled absorption system (TOCAS) with placebo or TOCAS monotherapy. The aim of the meta-analysis was to clarify the efficacy and safety of the combination treatments method for lower urinary tract symptoms (LUTS). We searched for trials of men with LUTS that were randomized to combination treatment compared with TOCAS monotherapy or placebo. We pooled data from three placebo-controlled trials meeting inclusion criteria. Primary outcomes of interest included changes in International Prostate Symptom Score (IPSS) and urinary frequency. We also assessed postvoid residual, maximum urinary flow rate, incidence of urinary retention (UR), adverse events. Data were pooled using random or fixed effect models for continuous outcomes and the Mantel–Haenszel method to generate risk ratio. Reductions in IPSS storage subscore and total urgency and frequency score (TUFS) were observed with solifenacin 6 mg plus TOCAS compared with placebo (P < 0.0001 and P < 0.0001, respectively). Reductions in IPSS storage subscore and TUFS were observed with solifenacin 9 mg plus TOCAS compared with placebo (P = 0.003 and P = 0.0006, respectively). Reductions in TUFS was observed with solifenacin 6 mg plus TOCAS compared with TOCAS (P = 0.01). Both combination treatments were well tolerated, with low incidence of UR. Solifenacin 6 mg plus TOCAS significantly improved total IPSS, storage and voiding symptoms compared with placebo. Solifenacin 6 mg plus TOCAS also improved storage symptoms compared with TOCAS alone. There was no additional benefit of solifenacin 9 mg compared with 6 mg when used in combination with TOCAS.

Absence of clinically relevant cardiovascular interaction upon add-on of mirabegron or tamsulosin to an established tamsulosin or mirabegron treatment in healthy middle-aged to elderly men.

Tamsulosin and mirabegron may be used concomitantly in patients with lower urinary tract symptoms. Since alpha1-adrenoceptor antagonists are associated with cardiovascular side effects, potential pharmacokinetic and cardiovascular interactions were evaluated. This was an open-label, randomized, 2-arm, 2-sequence study in 48 healthy men (24/arm) aged 44 - 72 years. In arm 1, subjects received single-dose tamsulosin hydrochloride modified release capsules (0.4 mg) alone and with steady-state mirabegron oral controlled absorption system tablets (100 mg once daily) in random sequence. In arm 2, subjects received single-dose mirabegron alone and with steady-state tamsulosin. Samples for mirabegron and tamsulosin plasma concentrations were collected. Blood pressure (BP) and pulse rate (PR) were measured and orthostatic stress tests were performed. Mirabegron increased tamsulosin C(max) to 159% (90% confidence interval (CI) 143 - 177%), AUC(∞) to 161% (90% CI 149 - 173%), and t(1/2) to 116%. Tamsulosin reduced mirabegron C(max) to 85% (90% CI 71 - 103%) and AUC(∞) to 84% (90% CI 74 - 95%) without effect on t1/2. Mirabegron and tamsulosin co-treatment caused no statistically significant changes (p > 0.05) in PR or systolic BP versus mono-treatment up to 12 hours post-dose. Mean diastolic BP decreases of -2.1 (95% CI -4.1, -0.1) to -4.2 (-7.5, -0.9) mmHg in arm 1 and -3.0 (-5.7, -0.3) to -4.2 (-7.4, -1.0) mmHg in arm 2 were observed, statistically significant (p < 0.05) at several time points, not accompanied by orthostatic symptoms or increases in positive orthostatic stress tests. Adverse and orthostatic events were balanced across treatments. The observed pharmacokinetic interactions upon add-on of mirabegron or tamsulosin to existing tamsulosin or mirabegron therapy did not cause clinically relevant changes in cardiovascular safety or safety profiles.

Long-term Safety and Efficacy of Single-tablet Combinations of Solifenacin and Tamsulosin Oral Controlled Absorption System in Men with Storage and Voiding Lower Urinary Tract Symptoms: Results from the NEPTUNE Study and NEPTUNE II Open-label Extension

BackgroundShort-term trials have demonstrated the efficacy and safety of combination therapy using antimuscarinics and α-blockers in men with lower urinary tract symptoms (LUTS). The Study of Solifenacin Succinate and Tamsulosin Hydrochloride OCAS (oral controlled absorption system) in Males with Lower Urinary Tract Symptoms (NEPTUNE) II is the first long-term study using solifenacin (Soli) and the oral controlled absorption system formulation of tamsulosin (TOCAS). ObjectiveTo evaluate long-term (up to 52 wk) safety and efficacy of flexible dosing of two fixed-dose combinations (FDC) of Soli plus TOCAS in men with moderate to severe storage symptoms and voiding symptoms. Design, setting, and participantsPatients with both storage and voiding LUTS, maximum urinary flow rate of 4.0–12.0ml/s, prostate size <75ml, and postvoid residuals ≤150ml, who completed the 12-wk, double-blind NEPTUNE study could continue in the 40-wk, open-label NEPTUNE II study. InterventionFDC of Soli 6mg plus TOCAS 0.4mg, or Soli 9mg plus TOCAS 0.4mg; patients could switch between doses in NEPTUNE II. Outcome measurements and statistical analysisSafety and efficacy data from NEPTUNE and NEPTUNE II were combined to cover a 52-wk period. Primary efficacy end points were total International Prostate Symptom Score (IPSS) and total urgency and frequency score (TUFS); secondary end points included IPSS storage and voiding subscores, micturition diary variables, and quality of life parameters. ResultsIn all, 1066 men completed NEPTUNE and received one dose or more of study medication in NEPTUNE II. Treatment-emergent adverse events were reported in 499 (46.8%) patients who participated in NEPTUNE II; most were mild or moderate. Urinary retention occurred in 13 of 1208 (1.1%) patients receiving one or more FDCs in NEPTUNE and/or NEPTUNE II; 8 (0.7%) required catheterisation (acute urinary retention [AUR]). Reductions in total IPSS and TUFS during NEPTUNE were maintained for up to 52 wk of FDC treatment, with mean reductions of 9.0 (standard deviation [SD]: 5.7) and 10.1 (SD: 9.2), respectively, from baseline to end of treatment. Clinically relevant improvements were also observed for secondary efficacy end points. ConclusionsLong-term treatment with FDC Soli plus TOCAS was well tolerated and efficacious in men with storage and voiding LUTS, with a low incidence of AUR. Patient summaryTreatment with solifenacin plus tamsulosin in a fixed-dose combination tablet was well tolerated by men with lower urinary tract symptoms. Improvements in symptoms were achieved after 4 wk of treatment, with further improvements at week 16 maintained for up to 52 wk throughout the study.

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy Japanese Male Subjects: Results from Single- and Multiple-Dose Studies

BackgroundMirabegron is a human β3-adrenoceptor agonist for the treatment of overactive bladder. The pharmacokinetic profile of mirabegron has been extensively characterized in healthy Caucasian subjects.ObjectiveThe objective of this study was to evaluate the pharmacokinetics, dose-proportionality, and tolerability of mirabegron following single and multiple oral doses in healthy Japanese male subjects. The results were compared with those reported in non-Japanese (primarily Caucasian) subjects.MethodsTwo studies were conducted. In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study (Study 1), mirabegron oral controlled absorption system (OCAS) tablets were administered at single doses of 50, 100, 200, 300, and 400 mg, with eight subjects (six active, two placebo) per dose group (Part I), and once daily for 7 days at 100 and 200 mg with 12 subjects (eight active, four placebo) per group (Part II). In an open-label, three-period, single-ascending dose study (Study 2), mirabegron OCAS was administered to 12 subjects at 25, 50, and 100 mg in an intra-subject dose-escalation design. Plasma and/or urine samples were collected up to 72 h after the first and last dose and analyzed for mirabegron. Pharmacokinetic parameters were determined using non-compartmental methods. Tolerability assessments included physical examinations, vital signs, 12-lead electrocardiogram, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event (AE) monitoring.ResultsForty and 24 young male subjects completed Part I and II, respectively, of Study 1. Twelve young males completed Study 2. After single oral doses (25–400 mg), maximum plasma concentrations (C max) were reached at approximately 2.8–4.0 h postdose. Plasma exposure (C max and area under the plasma concentration–time curve) of mirabegron increased more than dose proportionally at single doses of 25–100 mg and approximately dose proportionally at high doses of 300 and 400 mg. A more than dose proportional increase in plasma exposure was noted in the body of the same individual. Mirabegron accumulated twofold upon once-daily dosing relative to single-dose data. Steady state was reached within 7 days. Mirabegron was generally well-tolerated at single doses up to 400 mg and multiple doses up to 200 mg. The AE with the highest incidence was increased pulse rate at 400 mg in Study 1.ConclusionsMirabegron OCAS exhibits similar single- and multiple-dose pharmacokinetic characteristics and deviations from dose proportionality in healthy Japanese male subjects compared with those observed in non-Japanese (primarily Caucasian) subjects in previous studies.

Combination Therapy with Solifenacin and Tamsulosin Oral Controlled Absorption System in a Single Tablet for Lower Urinary Tract Symptoms in Men: Efficacy and Safety Results from the Randomised Controlled NEPTUNE Trial

BackgroundStorage symptoms are particularly bothersome in men with lower urinary tract symptoms (LUTS) but may not be adequately treated by α-blocker monotherapy. ObjectiveTo assess the efficacy and safety of a fixed-dose combination (FDC) of solifenacin and an oral controlled absorption system (OCAS) formulation of tamsulosin compared with placebo and compared with tamsulosin OCAS (TOCAS) monotherapy in men with moderate to severe storage symptoms and voiding symptoms. Design, setting, and participantsA double-blind 12-wk phase 3 study in 1334 men with storage and voiding LUTS: total International Prostate Symptom Score (IPSS) ≥13, maximum urinary flow rate (Qmax) 4.0–12.0ml/s, two or more urgency episodes per 24 h of Patient Perception of Intensity of Urgency Scale grade 3 or 4, and eight or more micturitions per 24h. InterventionPatients were randomised to placebo, TOCAS 0.4mg, FDC solifenacin 6mg plus TOCAS 0.4mg, or FDC solifenacin 9mg plus TOCAS 0.4mg. Outcome measurements and statistical analysisPrimary efficacy end points were (1) total IPSS and (2) Total Urgency and Frequency Score (TUFS). An FDC met the success criteria if it demonstrated superiority compared with placebo and noninferiority compared with TOCAS for total IPSS, as well as superiority compared with TOCAS for TUFS. Results and limitationsReductions in total IPSS and TUFS were observed with both solifenacin 6mg plus TOCAS (−7.0 and −8.1, respectively) and solifenacin 9mg plus TOCAS (−6.5 and −7.6, respectively) compared with TOCAS (−6.2 and −6.7, respectively) and placebo (−5.4 and −4.4, respectively). Solifenacin 6mg plus TOCAS met all prespecified success criteria for both primary end points, while solifenacin 9mg plus TOCAS met success criteria compared with placebo but not compared with TOCAS. Both FDCs improved quality of life (QoL) measures and were well tolerated, with low incidences of acute urinary retention. ConclusionsThe FDC of solifenacin 6mg plus TOCAS significantly improved storage and voiding symptoms, as well as QoL parameters, compared with placebo. This FDC also improved storage symptoms and QoL compared with TOCAS alone in men with moderate to severe storage symptoms and voiding symptoms, and it was well tolerated. Trial registrationClinicalTrials.gov Identifier: NCT01018511).

Role of Cytochrome P450 Isoenzymes 3A and 2D6 in the In Vivo Metabolism of Mirabegron, a β3-Adrenoceptor Agonist

Mirabegron is a β3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6. To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism. Two open-label, randomized, one-sequence crossover drug-drug interaction studies in healthy subjects were conducted to assess the effect of ketoconazole and rifampicin on the pharmacokinetics of mirabegron and two parallel-group studies in healthy subjects with either known confirmed or predicted CYP2D6 phenotype. Co-administration of multiple dosages of 400 mg/day ketoconazole with a single 100 mg mirabegron oral controlled absorption system (OCAS) dose increased mirabegron maximum concentration (C(max)) and area under the curve extrapolated to infinity (AUC∞) to 145 % (90 % confidence interval [CI] 123-172 %] and 181 % (90 % CI 163-201 %), respectively. Co-administration of multiple dosages of 600 mg/day rifampicin with a single 100 mg mirabegron OCAS dose decreased mirabegron C max and AUC∞ to 65 % (90 % CI 50-86 %) and 56 % (90 % CI 49-65 %), respectively, without an effect on terminal elimination half-life (t(½)). The urinary excretion of mirabegron was increased by ketoconazole and decreased by rifampicin, reflecting the AUC changes, whereas renal clearance was not affected. Ketoconazole decreased mirabegron t ½ from 50.9 to 37.6 h suggesting that volume of distribution as well as first-pass effect decreased. Rifampicin did not affect mirabegron t ½, suggesting that it affects first pass through the intestinal wall or liver. Rifampicin greatly increased the ratio to parent drug of the presumed CYP-mediated mirabegron metabolites M8 and M15 by 777 and 646 %. Steady-state mirabegron pharmacokinetic parameters (50 and 100 mg mirabegron OCAS) were similar in 13 CYP2D6 poor, 40 intermediate, and 99 extensive metabolizers, whereas C max and AUC under the dosing interval τ of 24 h (AUCτ) were 30-47 % lower in 10 ultrarapid metabolizers. After administration of 160 mg mirabegron immediate release, C(max) was 14 % and AUC∞ 19 % higher in eight poor metabolizers than in eight extensive metabolizers (phenotyped) with similar t ½. All treatments were well tolerated. Mirabegron is metabolized by CYP3A and to a minor extent by CYP2D6 in humans. Mirabegron is not considered a sensitive substrate of CYP3A in vivo, as ketoconazole increased mirabegron exposure by less than 2-fold. The effect of CYP2D6 phenotype on mirabegron exposure is small and likely of limited clinical importance.

Efficacy and Safety of Solifenacin Plus Tamsulosin OCAS in Men with Voiding and Storage Lower Urinary Tract Symptoms: Results from a Phase 2, Dose-finding Study (SATURN)

BackgroundStorage symptoms are often undertreated in men with lower urinary tract symptoms (LUTS). ObjectiveTo evaluate the combination of an antimuscarinic (solifenacin) with an α-blocker (tamsulosin) versus tamsulosin alone in the treatment of men with LUTS. Design, setting, and participantsA double-blind, 12-wk, phase 2 study in 937 men with LUTS (≥3 mo, total International Prostate Symptom Score [IPSS] ≥13, and maximum urinary flow rate 4.0–15.0ml/s). InterventionEight treatment groups: tamsulosin oral controlled absorption system (OCAS) 0.4mg; solifenacin 3, 6, or 9mg; solifenacin 3, 6 or 9mg plus tamsulosin OCAS 0.4mg; or placebo. Outcome measurements and statistical analysisThe primary efficacy end point was change from baseline in total IPSS. Secondary end points included micturition diary and quality-of-life (QoL) parameters. Post hoc subgroup analyses were performed by severity of baseline storage symptoms, with statistical comparisons presented only for tamsulosin OCAS alone versus combination therapy, due to the small sample size of the solifenacin monotherapy and placebo subgroups. Results and limitationsCombination therapy was associated with significant improvements in micturition frequency and voided volume versus tamsulosin OCAS alone in the total study population; improvements in total IPSS were not significant. Statistically significant improvements in urgency episodes, micturition frequency, total urgency score, voided volume, IPSS storage subscore, IPSS-QoL index, and Patient Perception of Bladder Condition were observed in a subpopulation of men with two or more urgency episodes per 24h (Patient Perception of Intensity of Urgency Scale grade 3 or 4) and eight or more micturitions per 24h at baseline (storage symptoms subgroup) with combination therapy versus tamsulosin OCAS alone (p≤0.05 for the dose–response slope, all variables). Combination therapy was well tolerated, and adverse events were consistent with the safety profiles of both compounds. ConclusionsSolifenacin plus tamsulosin OCAS did not significantly improve IPSS in the total study population but offered significant efficacy and QoL benefits over tamsulosin OCAS monotherapy in men with both voiding and storage symptoms at baseline. Combination therapy was well tolerated. ClinicalTrials.gov identifierNCT00510406

A phase II dose-ranging study of mirabegron in patients with overactive bladder

Introduction and hypothesisMirabegron is a potent and selective β3-adrenoceptor agonist that may represent an alternative treatment option in place of antimuscarinics for patients with overactive bladder.MethodsPatients completed a single-blinded, 2-week placebo run-in period followed by 12 weeks of randomized (n = 928) double-blinded treatment with mirabegron oral controlled absorption system (OCAS) 25, 50, 100, or 200 mg once-daily (QD), placebo or tolterodine extended release (ER) 4 mg QD. The primary endpoint was change from baseline to end-of-treatment in mean number of micturition episodes/24 h. Secondary endpoints included changes in mean volume voided per micturition; mean number of urinary incontinence, urgency urinary incontinence, and urgency episodes/24 h; severity of urgency; nocturia; and quality of life measures. Safety parameters included vital signs, adverse events, laboratory tests, electrocardiogram measurements and post-void residual volume.ResultsMirabegron 25, 50, 100, and 200 mg resulted in dose-dependent reductions (improvements) from baseline to end-of-treatment in micturition frequency of 1.9, 2.1, 2.1, and 2.2 micturitions/24 h respectively, versus 1.4 micturitions/24 h with placebo (p ≤ 0.05 for the mirabegron 50-, 100-, and 200-mg comparisons). There was a statistically significant improvement with mirabegron compared with placebo for most secondary endpoints including quality of life variables. While there was a significant (p < 0.05) increase from baseline in pulse rate in the mirabegron 100-mg and 200-mg groups, this was not associated with an increased incidence of cardiovascular adverse events.ConclusionsThe favorable efficacy and tolerability of mirabegron in this phase II dose-finding study has led to its successful advancement into a phase III clinical development program.

Effects of Food Intake on the Pharmacokinetic Properties of Mirabegron Oral Controlled-Absorption System: A Single-Dose, Randomized, Crossover Study in Healthy Adults

BackgroundMirabegron is a β3-adrenoceptor agonist used for the treatment of overactive bladder. Mirabegron is formulated as an extended-release tablet using oral controlled-absorption system (OCAS) technology. ObjectiveThis study was designed to assess the effects of food on the pharmacokinetic properties of mirabegron OCAS in accordance with regulatory requirements to support dosing recommendations. MethodsIn this single-dose, randomized, open-label, 3-period, parallel-dose-group, crossover study, mirabegron OCAS 50 or 100 mg was administered orally to healthy adult subjects in the fasted state or after a high- or low-fat breakfast. Dose administrations were separated by a washout period of at least 10 days. Blood samples were drawn up to 96 hours after dosing, and plasma concentrations of mirabegron were analyzed by LC/MS-MS. PK properties were determined using noncompartmental methods. Primary end points for the assessment of food effects were Cmax and AUC0–∞. For tolerability assessment, adverse events (AEs) were monitored using investigators' questionnaires and subjects' spontaneous reports, vital sign measurements, hematology, clinical chemistry, and ECG. ResultsThirty-eight subjects (male, 50%; mean age, 32.1 years; mean weight, 77.3 kg; race, 76.3% white) were enrolled in the 50-mg dose group and 38 subjects (male, 52.6%; mean age, 30.9 years; mean weight, 74.5 kg; race, 63.2% white) in the 100-mg dose group. With either fed condition or dose, the 90% CIs for the fed/fasted ratios of both Cmax and AUC0–∞ of mirabegron fell below the predetermined range for bioequivalence (80.0%–125.0%), suggesting that food had no effect on exposure to mirabegron OCAS. With the 50-mg dose, mirabegron Cmax was reduced by 45% with a high-fat breakfast compared with fasted conditions (geometric mean ratio [GMR], 54.8% [90% CI, 43.7%–68.6%]) and AUC0–∞, by 17% (GMR, 83.2% [90% CI, 74.2%–93.4%]). With the 100-mg dose, mirabegron Cmax and AUC0–∞ were reduced by 39% (GMR, 61.3% [90% CI, 47.8%–78.7%]) and 18% (82.4% [72.6%–93.5%]), respectively, after a high-fat breakfast. With the 50-mg dose, mirabegron Cmax was decreased by 75% (GMR, 25.0% [90% CI, 19.9%–31.3%]) and AUC0–∞ by 51% (48.7% [43.3%–54.7%]) after a low-fat breakfast. Corresponding reductions with the 100-mg dose were 64% (GMR, 36.3% [90% CI, 28.2%–46.8%]) for Cmax and 47% (GMR, 53.2% [90% CI, 46.8%–60.5%]) for AUC0–∞. The fed/fasted ratios for mirabegron Cmax and AUC0–∞ were in general independent of dose or sex. Food delayed Tmax compared with the fasted state, with similar increases with the high- and low-fat meals (0.9 hours with 50 mg and 1.5–2.0 hours with 100 mg). Mirabegron was generally well tolerated, with no apparent difference in AE frequency between the fasted and fed states. ConclusionsMirabegron OCAS tablets exhibited a decrease in mirabegron plasma exposure with food that was independent of dose (50 or 100 mg) or gender but dependent on meal composition. A greater reduction in mirabegron exposure was observed after a low-fat breakfast compared with after a high-fat breakfast. Based on findings from previous studies, the effects of food observed in this study do not warrant dose adjustment in clinical practice. ClinicalTrials.gov identifier: NCT00939757.

Pharmacokinetic Properties of Mirabegron, a β3-Adrenoceptor Agonist: Results From Two Phase I, Randomized, Multiple-Dose Studies in Healthy Young and Elderly Men and Women

BackgroundMirabegron (YM178) is a β3-adrenoceptor agonist for the treatment of overactive bladder (OAB). As part of the clinical development program for mirabegron, 2 human volunteer studies were performed to derive detailed data on the multiple-dose pharmacokinetic (PK) properties of mirabegron. ObjectiveTwo randomized Phase I studies were conducted to evaluate the PK properties of mirabegron, including metabolic profile and effects of age and sex, following multiple oral doses in healthy subjects. MethodsIn study 1, mirabegron oral controlled absorption system (OCAS) tablets were administered once daily to healthy young subjects (18–55 years) at doses of 50, 100, 200, and 300 mg and in elderly subjects (65–80 years) at 50 and 200 mg in a double-blind placebo-controlled, parallel-group design. In study 2, mirabegron OCAS was administered once daily to healthy young (18–45 years) and older (≥55 years) subjects at doses of 25, 50, and 100 mg in an open-label crossover design. Blood samples were collected up to 72 hours (study 1) and 168 hours (study 2) after the last dose. Urine samples were collected up to 24 hours after the last dose. Plasma and urine concentrations of mirabegron and its metabolites (study 2 only) were analyzed by LC-MS/MS. PK parameters were determined using noncompartmental methods. Tolerability assessments included physical examinations, supine blood pressure and pulse rate, orthostatic stress testing (study 1), resting 12-lead ECGs, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse-events (AE) monitoring using investigators' questionnaires and subjects' spontaneous reports. ResultsThirty-two young male (mean age, 30.3 years; mean weight, 77.1 kg), 32 young female (27.6 years; 64.6 kg), 16 elderly male (69.8 years; 79.3 kg), and 16 elderly female (68.1 years; 67.4 kg) subjects were enrolled in study 1. Eighteen young male (mean age, 28.6 years; mean weight, 68.9 kg), 18 young female (28.7 years; 58.8 kg), 21 older male (63.4 years; 72.6 kg), and 18 older female (65.1 years; 62.3 kg) subjects were enrolled in study 2. Most of the subjects were white (91% in study 1 and 88% in study 2). Mirabegron plasma concentrations peaked at ∼3 to 5 hours and declined multiexponentially with a t▪ of ∼32 hours in study 1 and 60 hours in study 2. Steady state was achieved within 7 days of once daily administration, with an accumulation ratio of ∼2. Mirabegron and its metabolites demonstrated a greater–than–dose-proportional increase in Cmax and AUC0–τ after multiple-dose administration. Two major circulating metabolites were observed, representing 17% and 10% of total drug-related AUC0–τ. Excretion of unchanged mirabegron in urine over the 24-hour dosing interval (Ae0–τ%) increased from approximately 7% at 25 mg to 18% at 300 mg once daily in young subjects. Renal clearance (CLR) of mirabegron was independent of dose and averaged ∼13 L/h. Mirabegron Cmax and AUC0–τ were similar in older and young subjects. Women exhibited ∼40% higher mirabegron Cmax and AUC0–τ than men; weight-corrected values were ∼20% higher in women. Mirabegron was generally well tolerated up to 300 mg once daily. No clear trends for increased incidence of AEs occurred with higher doses of mirabegron. The AE with the highest incidence was headache. ConclusionOral mirabegron exhibited a greater–than–dose-proportional increase in exposure. Sex but not age significantly affected mirabegron exposure. ClinicalTrials.gov identifier: NCT01478503 (Study 1) and NCT01285596 (Study 2).

Solifenacin Plus Tamsulosin Combination Treatment in Men With Lower Urinary Tract Symptoms and Bladder Outlet Obstruction: A Randomized Controlled Trial

BackgroundAlpha blockers are prescribed to manage lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Antimuscarinics are prescribed to treat overactive bladder (OAB). ObjectiveTo investigate the safety of a combination of solifenacin (SOLI) and tamsulosin oral controlled absorption system (TOCAS) in men with LUTS and bladder outlet obstruction (BOO). Design, setting, and participantsRandomized, double-blind, parallel-group, placebo-controlled study in men aged >45 yr with LUTS and BOO for ≥3 mo, total International Prostate Symptom Score (IPSS) ≥8, BOO index ≥20, maximum urinary flow rate (Qmax) ≤12ml/s, and voided volume ≥120ml. InterventionsOnce-daily coadministration of TOCAS 0.4mg plus SOLI 6mg, TOCAS 0.4mg plus SOLI 9mg, or placebo for 12 wk. Outcome measurements and statistical analysisPrimary (safety) measurements: Qmax and detrusor pressure at Qmax (PdetQmax). Other safety assessments included postvoid residual (PVR) volume. Secondary end points included bladder contractile index (BCI) score and percent bladder voiding efficiency (BVE). An analysis of covariance model compared each TOCAS plus SOLI combination with placebo. Results and limitationsBoth active treatment groups were noninferior to placebo at end of treatment (EOT) for PdetQmax and Qmax. Mean change from baseline PVR was significantly higher at all time points for TOCAS 0.4mg plus SOLI 6mg, and at weeks 2, 12, and EOT for TOCAS 0.4mg plus SOLI 9mg versus placebo. Both treatment groups were similar to placebo for BCI and BVE. Urinary retention was seen in only one patient receiving TOCAS 0.4mg plus SOLI 6mg. Limitations of the study were that prostate size and prostate-specific antigen level were not measured. ConclusionsTOCAS 0.4mg plus SOLI 6mg or 9mg was noninferior to placebo at EOT for PdetQmax and Qmax in men with LUTS and BOO, and there was no clinical or statistical evidence of increased risk of urinary retention.

Efficacy of Tamsulosin Oral Controlled Absorption System After Extracorporeal Shock Wave Lithotripsy to Treat Urolithiasis

To determine the efficacy of the tamsulosin oral controlled absorption system as an adjuvant therapy to extracorporeal shock wave lithotripsy (ESWL) for the expulsion of ureteral and renal stones. A consecutive sample of 248 patients with ureteral or renal stones who underwent ESWL in an academic hospital was included in a 12-week, prospective, open-label, randomized clinical trial. Of the 248 patients, 186, including 77 with ureteral stones (mean size 9 mm) and 109 with renal stones (mean size 13 mm) completed the study. After successful ESWL, the patients were randomized to standard medical care (corticosteroids and analgesics) or standard care plus the tamsulosin oral controlled absorption system 0.4 mg/d for 1 month. The stone clearance rate, interval to the elimination of stone fragments, incidence of renal colic, and the need for rehospitalization were assessed at 4, 8, and 12 weeks. The stone clearance rate was significantly greater for the patients treated with tamsulosin than for those in the standard care group at 4 (73.4% vs 55.9%, respectively; P < .001) and 12 (91.3% vs 74.6%, respectively; P < .05) weeks. Tamsulosin treatment was also associated with a significantly lower interval to the elimination of stone fragments (P < .001), a significantly lower rehospitalization rate (P < .001), and a significantly lower proportion of patients with acute renal colic (P < .05) than standard care alone. No severe adverse events leading to treatment discontinuation were observed. Adjuvant treatment with tamsulosin, in addition to standard treatment with steroids and analgesics, improved the outcome of ESWL.

MP-05.01 Evaluating the Efficacy and Safety of Fixed-Dose Combinations of Tamsulosin OCAS™ and Solifenacin in Male LUTS with Storage and Voiding Symptoms: An Overview of the NEPTUNE Trial

The use of combination therapy to treat the spectrum of male LUTS is receiving increasing attention. The phase 2 SATURN trial evaluated the effects of a combination of the oral controlled absorption system (OCAS) formulation of tamsulosin and solifenacin as a treatment for men with LUTS associated with BPH. The results showed that men who had both voiding symptoms and substantial storage symptoms at baseline benefited from combination therapy. A fixed-dose combination tablet incorporating tamsulosin OCAS and solifenacin is therefore being evaluated in the NEPTUNE trial.