Silodosin From Bench to Bedside: Selectivity, Safety, and Sustained Efficacy

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1 EUROPEAN UROLOGY SUPPLEMENTS 10 (2011) available at journal homepage: Silodosin From Bench to Bedside: Selectivity, Safety, and Sustained Efficacy Andrea Russo a,b, Petter Hedlund a,c, Francesco Montorsi a,b, * a Urological Research Institute, San Raffaele University, Milan, Italy b Department of Urology, San Raffaele University, Milan, Italy c Department of Clinical Pharmacology, Linköping University Hospital, Linköping, Sweden Article info Keywords: Adrenoceptor-a 1A Selective antagonist Improvement LUTS Prostate Silodosin a-blockers Benign prostatic hyperplasia BPH Abstract Context: Silodosin is the a 1 adrenoceptor (AR) antagonist with the highest selectivity for the a 1A -AR subtype that is available for the treatment of lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). How do preclinical findings translate into clinical effect? Objective: Analyse information on the preclinical selectivity profile of silodosin in relation to clinical efficacy and safety. Evidence acquisition: A Medline search for published articles on silodosin in preclinical and clinical studies was conducted. Information was also acquired from documents published by the European Medicines Agency. Evidence synthesis: Silodosin exhibits high selectivity for the a 1A subtype of the adrenoceptor, and it also displays selectivity for the lower urinary tract and prostate versus vascular functions as assessed in studies of isolated tissues, animal models, and patients. Silodosin causes symptom relief within days and is superior to placebo and noninferior to tamsulosin in reducing symptoms in patients with BPH. The effects of silodosin were sustained for wk in open-label extension studies of 1170 patients. The safety and tolerability of silodosin are excellent. Silodosin more frequently causes abnormal ejaculation than placebo or tamsulosin, although only a minority of the patients discontinues treatment due to this adverse event. Conclusions: Both preclinical and clinical studies support the contention that silodosin has high uroselectivity and a positive cardiovascular safety profile, likely related to its selectivity for the a 1A -AR subtype. Silodosin has a rapid onset of action and a sustained efficacy on LUTS due to BPH. # 2011 Published by Elsevier B.V. on behalf of European Association of Urology. * Corresponding author. Urological Research Institute, Department of Urology, San Raffaele University, Via Olgettina 40, Milan, Italy. Tel ; Fax: address: montorsi.francesco@hsr.it (F. Montorsi). 1. Introduction Lower urinary tract symptoms (LUTS) are common in men with benign prostatic hyperplasia (BPH), and they have a substantial impact on quality of life (QoL) [1,2]. The incidence of BPH is reported to be >80% in men 70 yr, and LUTS in men increase from 56% in men yr of age to 70% in men 80 yr of age [3]. The classical view of male LUTS involves coexisting BPH, where the enlarged prostate reduces the lumen of the prostatic urethra and causes benign prostatic obstruction (BPO) that compromises optimal urine flow during voiding [4]. Secondary changes to BPO that are also implicated in LUTS development include progressive denervation and hypertrophy of the bladder wall and changes of the urothelium. Data /$ see front matter # 2011 Published by Elsevier B.V. on behalf of European Association of Urology. doi: /j.eursup

2 446 EUROPEAN UROLOGY SUPPLEMENTS 10 (2011) from experimental models also suggest persistent changes in the central nervous regulation of the micturition reflex [4 6]. BPO is attributed both to the enlarged mass of the prostate and to a dynamic component related to the tone of the smooth muscle in the stroma of the prostate, urethra, and bladder neck [4]. The main tonus regulatory system of the outflow region consists of a dense adrenergic nerve supply and postjunctional a 1 -adrenoceptors (a 1 -ARs) [4]. The three currently cloned and characterised a 1 -AR subtypes, a 1A, a 1B,anda 1D, have all been located in the human prostate, and the a 1A -AR subtype is considered very important for contractile functions in both the normal and hyperplastic prostate [4]. Antagonism of a 1 -AR mediated tonus relaxes isolated normal and hyperplastic prostate tissue and a 1 -AR antagonists are clinically shown to be effective to improve maximum flow rate (Q max ) and symptoms compared with placebo in men with BPO [4,7,8]. The a 1 -AR mediated functions of other organs, mainly cardiovascular control, is of concern when using a 1 -AR in BPO [7]. Increased risks for developing any vascular event versus placebo were demonstrated for alfuzosin, terazosin, and doxazosin, whereas a nonsignificant numerical increase was reported for tamsulosin [7]. All a 1 -AR subtypes are expressed in various regions of the vascular bed, and in vivo, the a 1B -AR appears to be of particular importance for systemic blood pressure control [9]. Clinical interest in further improving the cardiovascular safety of a 1 -AR antagonists in BPO has focused attention on the development of subtype selective compounds. It is estimated that agents with 100-fold subtype selectivity ratios are necessary to translate experimental pharmacologic findings to the clinic. In addition, other factors, such as dose, drug kinetics, receptor distribution, and receptor activities in tissues, need consideration [10]. Of the currently clinically available a 1 -AR antagonists, silodosin is the only agent with a distinct selectivity for the a 1A -AR subtype [11]. Tamsulosin has some selectivity for the a 1A - versus the a 1B - but not for the a 1D -AR subtype, and other agents (eg, terazosin, alfuzosin, doxazosin) do not discriminate among a 1 -AR subtypes [12]. The pharmacokinetic properties of silodosin were recently described elsewhere [13,14]. The present review analyses published articles on silodosin with attention to its preclinical selectivity profile and its efficacy and safety in patients. 2. Evidence acquisition A Medline search including publications on the preclinical pharmacology, clinical efficacy, and safety of silodosin was conducted. Articles published from 1995 to 2011 were considered. Attention was given both to peer-reviewed published items for preclinical data on silodosin or related background information and to randomised, blinded, placebo- or active-control trials of silodosin. Information was also retrieved from official documents produced by the European Medicines Agency. Finally, although of a lower level of evidence, but to highlight relevant drug-related information or the need for further investigations, information was also obtained from open-label studies. 3. Evidence synthesis 3.1. Preclinical pharmacology Receptor selectivity In binding studies with cloned human a 1 -AR subtypes, silodosin exhibited substantial potency (Ki value: nm) and was highly selective for a 1A with 582- and 56-fold lower affinities for a 1B and a 1D than a 1A [11]. In comparison, prazosin or phentolamine did not discriminate between a 1 -AR subtypes, and tamsulosin exhibited a 15-fold lower affinity for a 1B than a 1A but with no difference for a 1D. Silodosin had a 10-fold higher affinity for the human cloned a 1A as compared with rat [11]. Whereas silodosin in radioligand binding experiments using human, rat, and hamster a 1 -AR subtypes exhibited affinity only for a 1A with insufficient activity at a 1B, and a 1D for an estimation of dissociation ratios, results for tamsulosin were similar to findings by Shibata et al [11] Tissue selectivity Silodosin discriminated between natively expressed a 1 -AR subtypes in human liver (a 1A, a 1B )andprostate(a 1A )with similar affinity values as obtained in studies with cloned receptors [11]. Radiolabelled silodosin showed similar subtype selectivity in rat tissues, that is, high affinity for a 1A (prostate) and no significant binding to a 1B (liver) [15]. In comparison, tamsulosin could not detect the two affinity sites, which the authors concluded was due to the lower selectivity of the compound [11]. Whereas radiolabelled silodosin saturated binding in prostate membranes with an affinity constant of 10.5 nm, binding of the compound in aortic membranes was too low to calculate affinity [16]. In competitive binding experiments, the affinities of silodosin, tamsulosin, and prazosin for the human prostate were 214-, 8.3-, and 0.3-fold higher than for the human aorta [16]. In pharmacologic studies of human- and rabbit-isolated prostate tissues, silodosin and tamsulosin inhibited functional a 1 -AR with similar potencies (ie, at similar concentrations) [17,18]. Indicating that silodosin acts differently in prostatic and arterial vascular tissues, silodosin counteracted a 1 -AR mediated contractions of the rabbit prostate at lower concentrations than in rabbit and rat aorta [17]. Whereas silodosin exhibited an 83-fold higher potency for the rabbit prostate as compared with the rat aorta, for example, prazosin and tamsulosin exhibited similar activities in either tissue [17] Functional selectivity in vivo In male rats, intravenous (IV), intraduodenal (ID), or oral silodosin effectively and dose-dependently reduced phenylephrine-induced intraurethral pressure (IUP) responses [19]. Effects on IUP were preserved 12, 18, and 24 h after oral administration of silodosin [19]. In this model, silodosin had greater uroselectivity than any of the other compounds examined (both IV and ID routes), and the rank order of hypotensive potency was tamsulosin, then prazosin, then terazosin, and then silodosin [19].

3 EUROPEAN UROLOGY SUPPLEMENTS 10 (2011) Silodosin also dose-dependently reduced IUP in response to activation of the hypogastric nerve in male dogs after IV or ID administration with no influence on pressures of the urinary bladder or on heart rate (HR) [20 22]. Similar to findings in rats, in comparison with prazosin, tamsulosin, or naftopidil, silodosin exhibited small effects on mean blood pressure in normal dogs or in dogs with spontaneous BPH, and silodosin had the highest uroselectivity of the investigated compounds [20 22]. Whereas the hypotensive effects of tamsulosin were potentiated by age, the beneficial effect of silodosin on IUP versus blood pressure was not different in young and old BPH dogs [22] Extraprostatic a 1 -adrenoceptors Several investigators have demonstrated a 1 -AR activities in areas of the brain and spinal cord that are involved in regulating micturition, and in preclinical models, it is proposed that central nervous a 1 -AR activities are upregulated and more relevant in detrusor overactivity, including in outflow obstruction [4,5]. Indicating a role for supraspinal a 1A -AR in the regulation of voiding, intracerebroventricular administration of silodosin has been demonstrated to increase micturition intervals and bladder capacity of both normal rats and rats with outflow obstruction with a more pronounced effect by the drug in the latter group of animals [23,24]. It has also been proposed that neuronal projections from the brain to the lumbosacral cord promotes sensory signals of the micturition reflex via a 1A -AR, and after intrathecal (IT) administration, silodosin dose-dependently prolonged micturition intervals [24,25]. In support for this, IV, intraarterial, or IT administration of silodosin dose-dependently increased bladder capacity at baseline and prolonged micturition intervals during experimental detrusor overactivity in normal rats but not in rats that were devoid of C-fibres after treatment with resiniferatoxin [26]. The urothelium is considered to be involved in the regulation of mechanoafferent functions of the micturition reflex, and various alterations within the urothelium and suburothelial space have been identified as significant contributors to the generation of LUTS [6]. The urothelium has been demonstrated to express a 1 -AR activities (including a 1A -AR), and a 1 -AR antagonists have been shown to reduce increased release of adenosine triphosphate from urothelial cells obtained from patients with BPH [27,28]. Although reported from a small amount of patient material, altered transcription of the a 1D -AR subtype, and also a trend for altered transcription of the a 1A -AR subtype in bladder mucosa from BPO patients with pronounced storage symptoms (in comparison with BPO patients with less storage symptoms) has been presented [29]. Suggesting a possible role for urothelial a 1A -AR in the regulation of micturition, intravesical silodosin abolished noradrenalineinduced shortening of micturition intervals in rats [28] Cardiovascular safety In 139 healthy male subjects, placebo or silodosin 8 or 24 mg once daily for 5 d did not affect HR, QTc interval, PR interval, or QRS complex, and did not cause any deviations of electrocardiogram morphology [30]. In efficacy trials, silodosin (8 mg once daily) was similar to findings with placebo reported with low frequencies of cardiovascularadverse events [31,32]. The percentages of patients who experienced dizziness were % (silodosin) and % (placebo), and headaches were reported by 0.9% (silodosin) and 2.4% (placebo) of patients [31,32]. Orthostatic hypotension was reported in 1.5% (silodosin) and 2.6% (placebo) of patients [31]. In the study by Chapple et al, silodosin did not have effects on heart rate, and no episodes in response to orthostatic tests were observed [32]. Ina study evaluating the effect of silodosin (4 or 8 mg once daily) on abacterial prostatitis, similar frequencies of dizziness and headache as placebo were noted for both doses [33]. Kawabe et al did not report any clinically significant differences of systolic/diastolic blood pressures between the silodosin and tamsulosin groups [34]. Chapple et al did not find any significant differences in blood pressures for silodosin or placebo, but they reported a minor reduction of supine systolic blood pressure ( 2.2 mm Hg; p = vs placebo) with tamsulosin (0.4 mg) [32]. In the open-label extension study by Marks et al in 2009, neither drug-related cardiac events nor corrected QT interval prolongation was observed with silodosin. Orthostatic hypotension and dizziness did not differ between silodosin versus placebo in original double-blind studies [35]. According to the European Medicines Agency s Committee for Medicinal Products for Human Use, clinical developmental safety data from patients receiving silodosin with concomitant antihypertensive therapy do not indicate an increase in the risk of orthostatic hypotension [36]. Coadministration of silodosin 8 mg and maximum therapeutic doses of sildenafil or tadalafil in healthy men caused no clinically important orthostatic changes in blood pressure or HR and no orthostatic symptoms [37] Clinical efficacy Placebo and/or active-control studies Marks et al randomised 923 patients 50 yr of age with an International Prostate Symptom Score (IPSS) 13 and a urine Q max of >4 and 15 ml/s to receive 8 mg silodosin or placebo once daily for 12 wk in two double-blind multicentre studies in the United States [31]. The primary end point was change of IPSS from baseline to the end of the study. Change in Q max was a secondary end point. Storage and voiding symptoms and QoL were also assessed. After only 3 4 d (0.5 wk) of treatment, patients receiving silodosin had improvements in total IPSS (silodosin 4.2; placebo 2.3; p < 0.001). At 12 wk, total IPSS for patients on silodosin was further improved compared with placebo. Silodosin was superior to placebo to reduce both storage and voiding IPSS subscores at 0.5 and 12 wk. From 2 to 6 h after the first dose, measurements of Q max revealed significant improvements compared with baseline for patients receiving silodosin (+2.8 ml/s) but not placebo. This effect was maintained to the end of the study. Silodosin

4 448 EUROPEAN UROLOGY SUPPLEMENTS 10 (2011) also improved QoL. At baseline, 66% of patients receiving silodosin or placebo reported to be mostly dissatisfied with their current condition, and at 12 wk, this value was decreased to 38% for silodosin and 54% for placebo [31]. In Europe, 955 men 50 yr of age (IPSS 13, Q max of >4 and 15 ml/s) were randomised to receive 8 mg silodosin, 0.4 mg tamsulosin, or placebo once daily for 12 wk in a multicentre double-blind parallel-group study [32]. With the primary efficacy parameter change from baseline in the total IPSS questionnaire score, the aim of the study was to show that silodosin was superior to placebo and noninferior to tamsulosin for reducing LUTS in patients with symptomatic BPH. Secondary efficacy parameters included improvement in IPSS storage and voiding symptoms, QoL (due to urinary symptoms), Q max, and responders (%) to treatment. Decreases of the total IPSS score were observed within the first 2 wk of treatment, and this effect was superior ( p < 0.001) for silodosin compared with placebo at the following study visits. In comparison with placebo, silodosin significantly increased the rate of responders from baseline to the end of the study, reduced IPSS storage and voiding subscores, and improved QoL [32]. Silodosin or tamsulosin had similar effects on these parameters. Although nonsignificant, larger increases in Q max compared with placebo were observed for both silodosin and tamsulosin. A beneficial effect of reducing nocturia in favour of silodosin over tamsulosin versus placebo was noted in a subgroup analysis of patients with this symptom at baseline [32]. In a preliminary report of a pooled analysis of the three trials conducted in Europe and the United States of 1266 patients with two or more nocturnal voids at baseline, treatment with silodosin significantly reduced nocturia by one or more episodes in 35% of patients (compared with 23% for placebo) [38]. Two recently published clinical trials investigated the efficacy on LUTS of silodosin in Asian men with BPH [34,39]. These studies are considered separately in this paper because the dose of tamsulosin used (0.2 mg daily) is not comparable with the recommended dose currently used in Europe and the United States. The two double-blind multicentre trials included 457 patients (50 yr, with IPSS 8, Q max 15 ml/s) and 209 patients (40 yr, with IPSS 13, Q max 15 ml/s), respectively, who received treatment for 12 wk. The primary efficacy end point was the change in the total IPSS from baseline; secondary end points were changes in Q max, IPSS voiding and storage scores, and QoL score. At 1 wk after the start of the treatment, silodosin was already superior to placebo in the reduction of total IPSS, and this effect was maintained throughout the study. Silodosin also exhibited superiority to placebo ( p < 0.001) in reducing IPSS storage and voiding subscores Open extension studies After completion of one of the two double-blind, placebocontrolled 12-wk studies of silodosin for symptomatic BPH in the United States, patients received silodosin 8 mg once daily for 40 wk. Mean IPSS change from baseline to week 40 was 4.5 ( p < ) for de novo treatment (347 patients previously allocated to placebo) and 1.6 ( p < 0.01) for 314 patients continuing silodosin treatment [35]. After the double-blind phase of the 12-wk European trial, 500 evaluable subjects were enrolled in an open-label phase. Although no statistical analysis has been presented, reduction of 2.7 of the IPSS total score was observed at the first visit after 14 wk in subjects previously treated with placebo, and a smaller improvement was observed in subjects previously treated with silodosin or tamsulosin ( 0.82 and 0.83, respectively). The treatment effect was maintained up to 52 wk. Similar findings were observed for the irritative and obstructive symptoms subscores [36] Other studies Four other open-label 4-wk or 3-mo studies of a total of 326 patients receiving 8 mg silodosin have been conducted and support findings in controlled studies that silodosin improves voiding and storage symptoms in patients with BPH and that this effect is similar to that of other a 1 -AR antagonists [40 43]. In an open-label study of 36 men with BPH who were referred for surgery due to severe BPH or failure with other a-ar antagonists, treatment with silodosin (4 mg twice daily) significantly decreased total IPSS, storage and voiding symptom subscores, postvoid residual urine and QoL score, and increased Q max after 1 12 mo of therapy [44]. In29of these patients, urodynamic investigations were performed that showed therapy with silodosin increased maximum cystometric capacity and removed detrusor overactivity in 40% of the patients. In pressure-flow studies conducted in 27 of the patients, the obstruction grade was improved in 56% of the patients, and detrusor opening pressure, detrusor pressure at Q max, and the bladder outlet obstruction index decreased ( p < 0.01) after silodosin therapy. There were no episodes of urinary retention during the study period, and 44% of the patients were taking silodosin for more than a year. The authors suggested that silodosin may be used to manage LUTS and to avoid invasive surgery in selected cases, but extended studies are needed to verify this report [44]. Similar findings were reported by others [40] Adverse events The rate of serious adverse events (AEs) in the placebocontrolled blinded studies in the United States and Europe was low, and only 3 of a total of 1878 patients reported a serious AE possibly related to the use of silodosin [31,32].The most common AE observed was retrograde or abnormal ejaculation that occurred in % of patients receiving silodosin compared with % for tamsulosin and 0 1.1% for placebo [31,32,39]. Only % of the patients who received silodosin discontinued treatment due to abnormal ejaculation [31,32,39], thus indicating that abnormal ejaculation may not be perceived as a substantially bothersome event in BPH patients with LUTS. Similarly, in a 40-wk multicentre placebo-controlled double-blind study in 418 patients of once-daily tamsulosin where the rate of abnormal ejaculation was 10% (tamsulosin 0.4 mg) and 26% (tamsulosin 0.8 mg), only one patient in the tamsulosin 0.8 mg group withdrew [45]. In an extended analysis of 923 patients in clinical trials with silodosin, most AEs labelled as

5 EUROPEAN UROLOGY SUPPLEMENTS 10 (2011) retrograde ejaculation were reported as orgasm with absence of seminal emission (23.4%), followed by orgasm with reduced semen quality or force (4.7%) and retrograde ejaculation (0.4%) [46]. This may be supported by findings of a semen volume decrease of 1.8 ml in a double-blind crossover study of 50 men who randomly received either a single dose of 4 mg of silodosin or placebo [47]. For tamsulosin, a 2.1-ml reduction of the semen amount expelled was reported in a double-blind randomised, three-way, 5-d treatment crossover study of 48 men who daily received 0.8 mg tamsulosin, 10 mg alfuzosin, and placebo [48]. Other AEs that occurred in >2% of patients who received silodosin were reported as mild and consisted of thirst, diarrhoea, nasopharyngitis, and nasal congestion, for example [32,34,39]. Cardiovascular safety and related AEs for silodosin were discussed previously. 4. Conclusions The a 1A -AR selectivity profile of silodosin, as determined in receptor-binding studies, is likely to be the main pharmacologic reason behind the low activity of the compound in vascular tissues and its high efficacy in the prostate tissue, as well as the low vascular activity and high uroselectivity observed in animal models. These findings have also been clearly confirmed in several clinical trials showing that silodosin has a rapid onset of action and sustained efficacy on LUTS due to BPH while exhibiting a very good cardiovascular safety profile. Conflicts of interest Petter Hedlund and Francesco Montorsi are consultants for Recordati. Andrea Russo has nothing to disclose. Funding support None. References [1] Girman CJ, Jacobsen SJ, Rhodes T, Guess HA, Roberts RO, Lieber MM. Association of health-related quality of life and benign prostatic enlargement. Eur Urol 1999;35: [2] Wei JT, Calhoun E, Jacobsen SJ. 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