Evidence for the efficacy and safety of tadalafil and finasteride in combination for the treatment of lower urinary tract symptoms and erectile dysfunction in men with benign prostatic hyperplasia

Abstract

Benign prostatic hyperplasia (BPH) is an age-related phenomenon associated with prostatic enlargement and bladder outlet obstruction that can cause significant lower urinary tract symptoms (LUTS). These LUTS have a negative impact on an individual’s quality of life, which is why treatment of symptomatic BPH has become a major priority. Although surgical interventions exist for treating BPH, pharmacological therapies are often preferred due to their minimal invasiveness and high degree of effectiveness. The three classes of drugs approved for treating BPH include α-blockers, 5-α-reductase inhibitors (5-ARIs) and phosphodiesterase 5 (PDE-5) inhibitors. Individually, each class of drug has been studied and shown to improve symptom relief through a variety of different mechanisms. A more recent focus has been on the development of combinatorial therapies that combine classes of drugs in order to provide maximal benefit. The mTOPS and CombAT studies were the first of their kind to examine whether the combination of 5-ARIs and α-blockers was more effective than monotherapy alone. Both studies found similar results in that the combinatorial therapy was superior to monotherapy. Over the last decade other combinatorial therapies have been at the forefront of investigation. One in particular is the combination of tadalafil, a PDE-5 inhibitor, with finasteride, a 5-ARI. Studies have shown that the combination of tadalafil and finasteride is a safe, effective, and well tolerated treatment for BPH. Evidence suggests that this combination may be particularly effective in reducing treatment-related sexual adverse events associated with 5-ARI treatments. The following review will explore in detail the current evidence surrounding treatment of BPH LUTS using tadalafil and finasteride.

Introduction

Benign prostatic hyperplasia (BPH) is a condition histopathologically characterized by hyperplasia of stromal and epithelial elements in the periurethral transitional zone of the prostate. The development of prostatic hyperplasia may or may not be associated with increases in urethral resistance, causing bladder outlet obstruction (BOO) and characteristic lower urinary tract symptoms (LUTS) [Roehrborn, 2005]. LUTS can be divided into two categories: obstructive and irritative symptoms. Obstructive symptoms include hesitancy, straining, weak stream, and incomplete emptying, whereas irritative symptoms include frequency, urgency, nocturia, and dysuria. BPH is an age-related phenomenon and has been found to occur in approximately 50–60% of men in their 60s and 80% of men in their 80s in autopsy studies [Girman, 1998]. The main area of prostatic enlargement in BPH is the transitional zone of the prostate, or the periurethral area, which is a likely contributing factor to BOO [Berry et al. 1984]. Traditional therapies for BPH included watchful waiting, transurethral resection of the prostate (TURP), as well as open prostatectomy, however surgical intervention for BPH is invasive and has considerable associated morbidity. There has since been an emergence of targeted medical therapy for the treatment of symptomatic BPH.

There are currently three major classes of medications available for the treatment of BPH. These classes include α-blockers, 5-α-reductase inhibitors (5-ARIs) and phosphodiesterase 5 (PDE-5) inhibitors. α-Blockers are the most widely used class of medication for LUTS related to BPH [Roehrborn, 2005]. Relaxation of the resting smooth muscle tone in the prostate is mediated through α₁-adrenergic receptor blockade and can lead to reduced LUTS score indexes and improved urinary flow rates [Roehrborn, 2005]. Unfortunately, this class of medication does not affect the progressive natural history of BPH since they do not influence prostate growth [Roehrborn, 2005]. The second major class of medications are the 5-ARIs, which will be discussed later in this review. These medications target the 5-α-reductase (5-AR) enzyme, responsible for catalyzing the conversion of testosterone to dihydrotestosterone (DHT) [Roehrborn, 2005]. A more recently approved third class of medication are PDE-5 inhibitors such as tadalafil (Cialis, Eli Lilly, Toronto, Ontario, Canada). This class of drugs promotes smooth muscle relaxation and arterial dilation by inhibiting the degradation of cyclic guanosine monophosphate (cGMP) [Corbin, 2004]. Studies have shown that treatment with tadalafil is safe and can statistically significantly improve International Prostate Symptom Score (IPSS) among subjects [Donatucci et al. 2011; Porst et al. 2011]. Consequently, it was approved for the treatment of BPH-associated LUTS as well as for the treatment of combined BPH and erectile dysfunction (ED) in October 2011. Although the exact link between LUTS related to BPH and ED is not yet completely understood, numerous studies have shown there is a high comorbidity between ED and LUTS. In fact, one study which analyzed over 4000 randomly selected men between the ages of 30 and 80 showed that the prevalence of LUTS in men suffering from ED was 72.2% compared with just 37.7% in men who did not report ED [Braun et al. 2003]. In another study investigating sexual function in men with symptomatic BPH, it was found that approximately 60% of men with LUTS reported low scores for erections on a sexual function questionnaire [Namasivayam et al. 1998]. Taken together, these studies show that ED affects a significant number of men experiencing symptomatic BPH.

The role of androgens has been implicated in BPH as men castrated before puberty do not develop BPH. As well, even though circulating levels of androgens decrease in aging men, intraprostatic DHT levels remain high [Andriole et al. 2004]. The androgen-signaling cascade begins with the production of androgens predominantly from the testes and from the adrenals to a lesser extent. 5-AR is a nuclear membrane bound enzyme that catalyzes the NADPH-dependent reduction of testosterone to DHT. In animal studies, DHT has been found to be twice as potent as testosterone, with a greater affinity for the androgen receptor (AR) [Wright et al. 1996]. Upon binding, the DHT-AR complex then dissociates from heat shock proteins within the nuclear membrane and binds to androgen response elements to induce androgen-responsive genes such as prostate specific antigen (PSA), platelet-derived growth factor, and epidermal growth factor [Rittmaster, 2008; Bartsch et al. 2000]. Though the exact role of testosterone and DHT in BPH is unknown, one hypothesis is through the modulation of prostatic stromal cell insulin-like growth factor axis and paracrine effects on prostatic epithelial cells [Le et al. 2006].

Benign prostatic hyperplasia management

Lifestyle changes and herbal medicine

Lifestyle modifications may help improve BPH-related symptoms. These include decreasing alcohol and caffeine consumption as well as decreasing fluids before bedtime to improve nocturia symptoms, and timed voiding. One meta-analysis [Boyle et al. 2000] suggested that the herbal medication saw palmetto may result in a small improvement in BPH-related symptoms, but more recent studies have suggested the benefit is no better than placebo [Bent et al. 2006]. Saw palmetto has minimal side effects and it appears to be a harmless herbal remedy that may result in a slight benefit in a few patients.

Pharmacotherapy

α-Blockers

The α-blockers work to relax the smooth muscle at the prostate and bladder neck by blocking α_1a-adrenergic receptors. By relaxing the smooth muscle at the prostate neck, the urinary channel is opened, which allows a less constricted urinary flow. α-Blockers have a quick onset of action, within 3–5 days; however, once the medication is stopped, symptoms usually return to pretreatment, baseline levels. There are five main α-blockers: two second-generation drugs, terazosin (Hytrin, Abbott Laboratories, Toronto, Ontario, Canada) and doxazosin (Cardura, Pfizer Inc, Saint-Laurent, Quebec, Canada) [MacDonald et al. 2004]; and three third-generation drugs, tamsulosin (Flomax, Boehringer Ingelheim Ltd, Burlington, Ontario, Canada), alfuzosin (Xatral, Sanofi-Aventis, Laval, Quebec, Canada), and silodosin (Rapaflo, Actavis Inc, Mississauga, Ontario, Canada) [MacDonald and Wilt, 2005]. Both terazosin and doxazosin require dose titration because of their antihypertensive properties. Tamsulosin, alfuzosin, and silodosin usually do not require dose titration and have fewer cardiovascular side effects [Milani and Djavan, 2005]. All five agents are generally equally effective [Djavan and Marberger, 1999] and their side effects include light headedness from orthostatic hypotension (5–10% of patients), dizziness (5–10%), weakness (5%), headache (5%), asthenia (5–10%), nasal congestion (5%), and retrograde ejaculation (3–10%) [MacDonald et al. 2004]. Although α-blockers improve urine flow quickly, they do not reduce prostate size, and as a result they do not reduce the risk of future urinary retention or the need for BPH-related surgery [Kaplan et al. 2006]. In patients with severe allergies to sulfa, an allergic reaction to tamsulosin has been reported, and therefore this drug should be avoided in such patients.

Silodosin (Rapaflo, Actavis Inc, Mississauga, Ontario, Canada) is a super-selective α-blocker that has recently become available in Canada. This drug blocks α_1a-adrenergic receptors and, to a much lesser degree, α_1b and α_1d receptors. The heightened selectivity of silodosin may result in fewer cardiovascular side effects, which are mainly regulated by α_1b receptors [Kawabe et al. 2006]. A number of studies have confirmed the safety of silodosin, especially in terms of cardiovascular safety. There are negligible effects on heart rate or electrocardiogram, including PR segment and QRS complex [Montorsi, 2010]. Side effects include upper respiratory tract infection (2–19% of patients), diarrhea (2–7%), dizziness (3–5%), and orthostatic hypotension (3%). Alterations in ejaculatory function range from 5% to 28%, with a median of 20% of patients experiencing retrograde ejaculation. However, only about 2% of patients discontinued silodosin therapy based on ejaculatory dysfunction alone [Morganroth et al. 2010].

A major study comparing silodosin with tamsulosin was published in Europe [Chapple et al. 2011] and involved 1228 patients randomized to tamsulosin versus silodosin versus placebo for 12 weeks. This study found no significant differences between tamsulosin and silodosin in terms of IPSS for storage or voiding symptoms, which suggests that both drugs are equally efficacious in the treatment of BPH. Two other studies [Miyakita et al. 2010] have suggested that silodosin may be more effective than tamsulosin, but in both these studies suboptimal dosing of tamsulosin (0.2 mg daily) was used as the comparator. Ejaculatory dysfunction was higher in the silodosin group (14.2%) versus the tamsulosin group (2.1%). Interestingly, patients with ejaculatory dysfunction had the highest efficacy with silodosin, suggesting that the presence of ejaculatory dysfunction can be used as a surrogate for efficacy [Homma et al. 2010]. Cardiovascular side effects were comparable for both groups, and although silodosin demonstrated a more favorable cardiovascular profile than tamsulosin, this difference was not statistically significant. Recent studies have suggested that silodosin may have a quicker onset of action than tamsulosin [Homma et al. 2010].

5α-Reductase inhibitors

There are two main isoforms of 5-AR: the type 1 isoform is mainly found in the peripheral skin as well as the liver, whereas the type 2 isoform is the major enzyme in the genital tissues and hair follicles [Russell and Wilson, 1994]. Both isoforms are found in all zones of normal prostatic tissue; however, in BPH the type 2 isoform was found to be in significantly higher concentrations in the transition zone of the prostate [Iehlé et al. 1999]. It was also found that there was a significantly higher concentration of the type 1 isoform in prostate cancer specimens [Thomas et al. 2003], with under expression of type 2 in prostate cancer versus BPH or normal prostates [Luo et al. 2003]. Furthermore, congenital type 2 5-AR deficiency results in patients with prostates that remain small and entirely composed of stromal tissue [Imperato-McGinley et al. 1992; Sinnecker et al. 1996], leading the further investigation into the role of 5-AR inhibition in the treatment of androgen-dependent aberrant prostatic hyperplasia seen in BPH.

The 5-ARIs inhibit the conversion of testosterone to DHT, the main mediator of BPH progression. This causes the prostate to decrease in size and slow the progress of prostate growth [Roehrborn et al. 2002]. The onset of action with 5-ARIs is slower than with α-blockers, usually taking 4–6 months. The two main 5-ARIs are finasteride (Proscar, Merck & Co, Kirkland, Quebec, Canada) and dutasteride (Avodart, GlaxoSmithKline Inc, Mississauga, Ontario, Canada) [Bartsch et al. 2000; Clark et al. 2004]. Finasteride inhibits the type 2 5-AR isoform, whereas dutasteride inhibits both type 1 and type 2 isoforms. With this dual blockade, dutasteride lowers DHT production in the prostate by over 90%, whereas finasteride lowers DHT by 70% [McConnell et al. 1998]. As a result, dutasteride may have a faster onset of action than finasteride, but it is believed there are no long-term benefits to the increased DHT suppression achieved with dutasteride [Nickel et al. 2011]. The 5-ARI side effects include ED (in 5–8% of patients), ejaculatory dysfunction (1–5%), decreased libido (5%), and, rarely, gynecomastia (1%). By shrinking the prostate, the 5-ARIs have been shown to improve BPH-related symptoms and to reduce the risk of future urinary retention and BPH-related surgery [Roehrborn et al. 2002].

To date, no long-term comparison studies have been conducted between the commercially available 5-ARIs, dutasteride and finasteride. There have only been limited data from a single 1-year study comparing the two. The Enlarged Prostate International Comparator study is the only prospective, multicenter, randomized, double-blind, double-dummy, 12-month parallel-group study of orally administered daily finasteride versus dutasteride for BPH [Nickel et al. 2011]. It involved a total of 1630 men, randomized 1:1 to either 5 mg oral finasteride or 0.5 mg oral dutasteride administered daily. After the 12-month double-blinded phase, patients had an option to enroll in a 24-month open-label phase where patients all received dutasteride 0.5 mg once daily. This study demonstrated that over a 1-year period, dutasteride and finasteride show no statistically significant difference and are equally effective in reducing prostate size, improving maximum urinary flow rate (Q_max), as well as improving voiding symptoms associated with BPH, with similar rates of adverse events (AEs) [Nickel et al. 2011].

While, α-blockers do not affect PSA and have no effect on prostate cancer risk, the 5-ARIs lower PSA by 50% after 6 months on therapy [Debruyne et al. 2004]. Therefore, if a patient’s PSA is 8 ng/ml prior to the initiation of a 5-ARI, then after 4–6 months of therapy, the PSA should be in the 4 ng/ml range. While continuing on 5-ARI the PSA value should stay around this level. If the PSA rises on 5-ARI then a referral to a urologist is mandatory to exclude the development of new prostate cancer. While the patient is receiving a 5-ARI, the prostate should be checked with an annual digital rectal exam (DRE).

Controversy still exists about the increased risk of developing high-grade prostate cancer in patients taking a 5-ARI such as finasteride or dutasteride. Health Canada and the US Food and Drug Administration issued a label change for finasteride and dutasteride to include new safety information about the possible increased risk of being diagnosed with high-grade prostate cancer while on these agents, based on analysis of data from the Prostate Cancer Prevention Trial (PCPT) [Health Canada, 2012] and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial [Roehrborn et al. 2011]. Some experts have proposed that the increased risk of high-grade prostate cancer may be an artifact resulting from the interpretation of prostate biopsies in these studies. Current recommendations are to exclude prostate cancer in patients with BPH (based on PSA and DRE) prior to initiating 5-ARI for BPH.

Phosphodiesterase 5 inhibitors

As previously stated, ED and LUTS related to BPH often coexist in aging men [McVary and McKenna, 2004]. BPH not only causes prostatic obstruction and bladder neck contraction, but it may also alter smooth muscle relaxation, reduce blood flow, and reduce the function of nerves and the endothelium [McVary et al. 2007a]. A number of pathophysiological mechanisms support the relationship between LUTS and ED. For example, a reduction in nitric oxide synthase (NOS) containing nerves and increased Rho-kinase activity are both observed in men with LUTS and can lead to ED [McVary, 2006]. Fewer NOS-containing nerves make it more difficult to produce nitric oxide (NO), which is involved in activating guanylate cyclase, an enzyme that generates cGMP. Typically, cGMP will go on to stimulate smooth muscle relaxation and arterial dilation in order to cause erections [McVary, 2006]. Under normal conditions, PDE-5 promotes smooth muscle contraction by degrading cGMP; therefore, PDE-5 inhibitors can facilitate smooth muscle relaxation in men with BPH by inhibiting its degradation [Corbin, 2004]. Recent studies of oral PDE-5 inhibitors, including tadalafil, vardenafil (Levitra, Bayer HealthCare Pharmaceuticals Inc, Mississauga, Ontario, Canada), and sildenafil (Viagra, Pfizer Inc, Saint-Laurent, Quebec, Canada), have demonstrated significant improvements of LUTS in patients with BPH [McVary et al. 2007a; Stief et al. 2008; Tamimi et al. 2010]. A dosage of 5 mg tadalafil/day significantly improved IPSS compared with placebo [Egerdie et al. 2012], with improvement onset occurring within 2 weeks. Although urodynamic profiles were not significantly improved with daily tadalafil, patients’ symptom scores improved and side effects were minimal, including headache, back pain, facial flushing, dyspepsia, and nasopharyngitis.

Combination therapy

Studies have shown the benefit of combination therapy with 5-ARIs and α-blockers [Gormley et al. 1992). The benefit is greatest in patients with large prostates, where the 5-ARI shrinks the prostate and the α-blocker relaxes the smooth muscle of the prostate providing combination benefits. For patients with smaller prostates, α-blockers alone may be sufficient to alleviate urinary symptoms. Two landmark studies examined combination therapy for BPH: the Medical Therapy of Prostate Symptoms (mTOPS) study and the Combination of Avodart and Tamsulosin (CombAT) study.

The mTOPS study was a landmark trial comparing monotherapy with an α-blocker (doxazosin) or a 5-ARI (finasteride) versus combination therapy (doxazosin and finasteride) for BPH [McConnell et al. 2003]. This study randomized patients into four treatment groups: an α-blocker (doxazosin) alone, a 5-ARI (finasteride) alone, combination therapy, and placebo [McConnell et al. 2003]. Combination therapy provided the most effective increase in flow rate, improvement in symptom scores, reduction in risk of acute urinary retention (AUR), and reduction in the need for surgery. Prostate volume decreased in patients who received finasteride alone, and in patients who were treated with finasteride plus an α-blocker. Patients who were treated with an α-blocker alone or with placebo had an increased prostate volume over time, and they did not have a reduced need for future BPH-related surgery or a reduced risk of developing AUR.

The CombAT study was designed to examine whether the combination of a 5-ARI (dutasteride) and an α-blocker (tamsulosin) was more effective than monotherapy alone for improving symptoms for men who had BPH, or to prevent the progression of BPH [Roehrborn et al. 2009]. A total of 4844 patients were randomized 1:1:1 to combination 0.5 mg dutasteride once daily and 0.4 mg tamsulosin once daily (n = 1610), 0.5 mg dutasteride once daily with tamsulosin matched placebo once daily (n = 1623), or 0.4 mg tamsulosin with dutasteride matched placebo once daily (n = 1611). There was no double placebo group as both monotherapies had established efficacy, so it was considered unethical to treat this patient group with placebo for 4 years. The study was powered at 94% at year 4 for the primary comparison of combination therapy versus tamsulosin. The 4-year results and the 2-year results showed that there was an improvement in the quality of life and an improvement in symptom scores in men with proven, enlarged prostates that were larger than 30 ml [Roehrborn et al. 2009]. With improvement on combination therapy, in most cases men were able to stop taking the α-blocker after 6–9 months [Roehrborn et al. 2009]. After stopping the α-blocker most of the men were still able to maintain a fairly good, symptom-free response. Jalyn, a single-capsule combination of dutasteride 0.5 mg and tamsulosin 0.4 mg, was approved for use in men with symptomatic BPH based on the study results from the CombAT trial.

The standard therapy for managing a patient with BPH is initiating an α-blocker with a quick onset of action, between 3 and 5 days. Selective α-blockers include tamsulosin, alfuzosin, and more recently, silodosin. For patients with larger prostates, the addition of a 5-ARI such as finasteride or dutasteride may be considered to reduce prostate volume, reduce the risk of AUR, and decrease the risk of future prostate-related surgery. After 6–9 months of combination therapy with an α-blocker and a 5-ARI, physicians may consider stopping the α-blocker. In addition to treating patients with BPH with drugs from the 5-ARI class and the α-blocker class, drugs from the PDE-5 inhibitor class may now be considered for treating BPH. Once daily tadalafil 5 mg has been shown to improve BPH-related symptoms and is a current treatment option for patients.

In the mTOPS and CombAT studies the therapeutic potential of combining certain 5-ARIs with α-blockers was evaluated. The positive results achieved in both of these landmark studies have opened the door to more research into combinatorial pharmacotherapies. This review will investigate whether there is a similar therapeutic benefit in treating men with BPH using the combined treatment of 5-ARIs and PDE-5 inhibitors. Specifically, this review will focus on evaluating the efficacy and safety of tadalafil and finasteride in the treatment of LUTS and ED in men with BPH.

Tadalafil and finasteride combinatorial treatment

Tadalafil

Tadalafil is an orally administered synthetic carboline-based compound with vasodilatory activity and the chemical name of (6R-trans)-6-(1,3-benzodioxol-5-yl)- 2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino [1′, 2′:1,6] pyrido[3,4-b]indole-1,4-dione [National Center for Biotechnology, 2015a]. Tadalafil selectively inhibits the PDE-5-mediated cGMP degradation in the corpus cavernosum. In turn, the increased levels of cGMP promote prolonged muscle relaxation, vasodilation, and blood engorgement of the corpus cavernosa leading to prolonged penile erection and potential improvement of LUTS caused by BPH [National Center for Biotechnology, 2015a]. The NO cascade is the major physiological process that is targeted by tadalafil. Typically this cascade leads to the activation of guanylate cyclase, which in turn produces an increase cGMP. This molecule has a variety of roles in the body, but most importantly it stimulates vasodilation. Under normal conditions cGMP is degraded by PDE-5, but by inhibiting this enzyme, tadalafil allows cGMP to exist in higher levels and exert beneficial vasodilatory activity [Curran and Keating, 2003]. In Canada, 5 mg daily tadalafil was approved for the treatment of BPH and ED, as of June 2012.

Pharmacodynamics

Clinical trials have shown that through the inhibition of PDE-5, tadalafil can greatly improve clinically relevant measures of LUTS secondary to BPH along with erectile function (EF) in those who are sexually active and suffering from ED [McVary et al. 2007b; Roehrborn et al. 2008; Oelke et al. 2012]. Several double-blind, placebo-controlled, randomized controlled trials (RCTs) have already been conducted and their results are remarkably consistent. Tadalafil seems to significantly improve the mean change from baseline in IPSS as early as 1–2 weeks after beginning treatment [Oelke et al. 2012; Egerdie et al. 2012]. In one study looking at four clinically relevant doses of tadalafil, the IPSS least squares mean change from baseline to end point was significantly improved for 2.5 mg (−3.9), 5 mg (−4.9), 10 mg (−5.2), and 20 mg (−5.2) of daily tadalafil compared with placebo (−2.3) [Roehrborn et al. 2008]. In another RCT it was found that tadalafil significantly improved the mean change from baseline in IPSS at 6 weeks for 5 mg tadalafil (−2.8 versus placebo −1.2) and at 12 weeks for 5/20 mg tadalafil (−3.8 versus placebo −1.7) [McVary et al. 2007b]. Studies suggests that a three-point change in the IPSS represents the minimum clinically meaningful change [Barry et al. 1995] and we see changes approaching this threshold in many of the participant groups in these two studies.

Besides changes in IPSS, other secondary measures are also significantly improved by treatment with tadalafil. These include IPSS irritative and obstructive domains, IPSS quality of life index (IPSS QOL), BPH Impact Index (BII) and also the International Index of Erectile Function within the erectile function domain (IIEF-EF) [McVary et al. 2007b; Roehrborn et al. 2008]. In one study 56% of men with BPH LUTS who were sexually active and suffering from ED saw significant improvements in their IIEF-EF scores [McVary et al. 2007b]. Similar results were also found in the four-dose tadalafil RCT among this subset of men in the study [Roehrborn et al. 2008]. There is still some debate as to whether tadalafil can improve uroflowmetry parameters such as Q_max. Several studies have shown a numerical improvement in this parameter in groups of subjects taking tadalafil; however, the improvement was not statistically significant [McVary et al. 2007b; Roehrborn et al. 2008]. Recently, in an international RCT the mean change in Q_max among men taking 5 mg of tadalafil for 12 weeks was 2.4 ml/s, which was statistically significant higher than the placebo control group [Oelke et al. 2012]. Researchers in this study were conservative in stating that these findings could have been random or due to their study population starting with lower baseline Q_max values. In addition, BPH guidelines state that there is a poor correlation between symptoms and Q_max [Oelke et al. 2012]. Nonetheless, in vitro studies have shown that PDE inhibitors can induce smooth muscle relaxation in the human bladder neck and prostate, which may promote the increase observed in Q_max values in these studies [Uckert et al. 2008].

Pharmacokinetics and metabolism

As with other PDE-5 inhibitors, tadalafil is rapidly absorbed after oral administration; it has a t_max of approximately 2 h and an onset time of 30–120 min post dose [Mehrotra et al. 2007; Eardley and Cartledge, 2002]. Studies have found that the peak plasma concentration of tadalafil (C_max) was 378 μg/liter following a therapeutic 20 mg dose administration [Rosen and Kostis, 2003; Sussman, 2004]. Although tadalafil’s absolute bioavailability has not been reported, it is known that at least 36% of the dose is absorbed from an oral solution [Mehrotra et al. 2007]. The absorption and other pharmacodynamic properties of tadalafil are unaffected by food intake prior to administration [Brock, 2003]. Furthermore, it is highly plasma protein bound (94%) and the two principle plasma proteins to which it binds are albumin and α1 acid glycoprotein [Mehrotra et al. 2007]. There is high distribution observed as well for tadalafil, with an apparent volume of distribution of 60–70 liters [Curran and Keating, 2003]. Metabolism of tadalafil mainly occurs through the cytochrome P450 3A (CYP3A4) oxidative process. Unlike other PDE-5 inhibitors such as vardnafil and sildenafil, which are metabolized into more than 10 different metabolites, tadalafil is primarily metabolized by CYP3A4 to a single catechol metabolite. This catechol metabolite then undergoes methylation and glucuronidation to form methylcatechol and methylcatechol glucuronide metabolites [Mehrotra et al. 2007]. The major tadalafil metabolite in the plasma is inactive; in fact its affinity towards PDE-5 is 10,000 fold less [Curran and Keating, 2003]. In contrast, many of the metabolites of vardnafil and sildenafil have major activity and contribute to the overall efficacy and safety profile of these drugs [Cheitlin et al. 1999]. When it comes to the elimination of tadalafil, the primary route is through hepatic metabolism and renal excretion of the unchanged drug. For the most part, oral tadalafil is excreted through feces (61%) as inactive metabolites, but some is also excreted through the urine (36%) [Curran and Keating, 2003]. Additionally, tadalafil has a low hepatic extraction ratio with a mean oral clearance of 2.5 liter/h in healthy subjects. Due to its low systemic clearance rate relative to other PDE-5 inhibitors, tadalafil has a much higher half life at approximately 17.5 h [Mehrotra et al. 2007; Meibohm and Derendorf, 1997].

Finasteride

Finasteride is an orally administered synthetic 4-azasteroid compound and its chemical name is N-(1,1-dimethylethyl)-3-oxo-(5α,17β)-4-azaandrost-1-ene-17-carboxamide [National Center for Biotechnology, 2015b]. It is a competitive and selective inhibitor of the type 2, 5-AR isoenzyme, which is an intracellular enzyme that converts testosterone to DHT [Bartsch et al. 2000]. The reduction in serum DHT levels results in diminished stimulation of ARs in the nuclei of prostate cells and consequently diminished prostate cell proliferation [National Center for Biotechnology, 2015b]. Approval by the US Food and Drug Administration was obtained in 1992 as monotherapy for the treatment of symptomatic BPH.

Pharmacodynamics

Many clinical trials have sought to analyze the effects of finasteride in vivo. Through its ability to selectively and competitively inhibit the type 2 5-AR isoenzyme, finasteride can have a significant impact on levels of DHT within the body. Type 2 5-AR is the predominant isoenzyme found in prostatic tissue [Wilde and Goa, 1999], which helps to explain why the greatest reduction in DHT is observed in prostatic tissue. It has been found that finasteride can reduce prostatic DHT levels over 90%, but only circulating DHT levels by 60–80% [Wilde and Goa, 1999]. These results are congruent to those found in a double-blind, placebo-controlled RCT that measured levels of prostatic DHT following a 7-day daily treatment of finasteride at either 1, 5, 10, 50, or 100 mg/day. Regardless of the dose given, prostatic DHT levels declined to 15% or less of the control levels within 1 week of treatment [McConnell et al. 1992]. Interestingly, in both of these studies prostatic testosterone levels seem to increase in a reciprocal manner yet have no significant ability to affect prostatic growth or morphology [Wilde and Goa, 1999; McConnell et al. 1992]. Meanwhile, the decrease in DHT had a multitude of effects, including an apparent reduction in prostate size through finasteride-induced atrophy and apoptosis after 6 months of treatment [Wilde and Goa, 1999]. Besides lowering DHT levels in the prostate and to a lesser extent in the serum, a double-blind, placebo-controlled, randomized trial in which 5 mg finasteride was administered daily to a group of men with BPH showed that it could also significantly reduce total BPH symptom score and increase Q_max [Andersen et al. 1995]. The maximum urinary flow rate decreased in the placebo group by 19%, but improved in the finasteride group by 12%, leading to a between-group difference that was statistically significant (1.8 ml/s) [Andersen et al. 1995]. Furthermore, a pooled analysis of RCTs with 2-year follow-up data comparing finasteride with placebo was performed to analyze differences in AUR and BPH-related surgical interventions. Results from the pooled analysis show that treatment with finasteride for 2 years reduced the frequency of AUR by 57% and also significantly decreased the frequency of surgical interventions (4.2% in the finasteride group versus 6.5% in the placebo group) [Andersen et al. 1997]. This study is particularly important as it supports the idea that finasteride can improve the long-term management of BPH.

Pharmacokinetics and metabolism

Finasteride is rapidly absorbed after oral administration and it has a t_max of 2 h when mean peak plasma concentrations are achieved [Carlin et al. 1992]. Food was shown to slow the rate of absorption, but not the overall extent, and this has not been shown to be clinically significant [Wilde and Goa, 1999]. Finasteride has been shown to have a bioavailability of 80% after oral administration and demonstrates dose proportionality in plasma concentrations [Carlin et al. 1992]. In addition, it is highly plasma protein bound (90%), mainly to albumin and α1 acid glycoprotein [Carlin et al. 1992]. There is extensive distribution of drug observed, with a steady-state volume of distribution of 76 liters [Wilde and Goa, 1999]. In vitro studies have shown that finasteride is metabolized through an oxidative process by CYP450, specifically by the 3A4 and 2C19 isoenzymes [Chen et al. 2009]. Finasteride is extensively metabolized in the liver to essentially inactive metabolites, including ω-hydroxyfinasteride and fineasteride-ω-oic acid [Lundahl et al. 2009]. The majority of an oral dose is excreted through feces and bile (75%) compared with the urine (25%) and its half life is reported to be approximately 9 h [Wilde and Goa, 1999; Carlin et al. 1992].

Therapeutic trials

To date, several clinical trials have been done using a combinatorial treatment of tadalafil and finasteride [Casabé et al. 2014; Roehrborn et al. 2015; Elkelany et al. 2015]. The first placebo-controlled study was an international randomized, controlled, double-blind study in men who were over 45 years old with a baseline IPSS of 13 or greater and prostate volume of 30 ml or greater [Casabé et al. 2014]. The study was conducted from November 2010 to September 2012 and randomized participants to two different groups: once daily placebo/5 mg finasteride (n = 350) (PBO/FIN) and once daily 5 mg tadalafil/5 mg finasteride (n = 346) (TAD/FIN) for 26 weeks. IPSS and IIEF-EF were used to assess changes in LUTS and EF, respectively, in order to evaluate whether the combinatorial therapy was superior to finasteride alone. Of the 696 participants randomized, 659 completed 12 weeks of therapy and 592 completed all 26 weeks [TAD/FIN 306 (88.4%) and PBO/FIN 286 (81.7%)]. TAD/FIN combinatorial therapy led to significant improvements in IPSS total scores compared with those on the finasteride monotherapy after 4, 12, and 26 weeks. The least squares (LS) mean change from baseline with TAD/FIN at 12 weeks was −5.2 versus –3.8 for PBO/FIN, which represents a least squares total difference (LSTD) of −1.4 (p < 0.001). Significant LSTD were observed in the 4- and 26-week time points as well, specifically they were −1.7 and −1.0, respectively.

Another primary outcome evaluated by this study was EF among sexually active patients who had ED at baseline (n = 201 PBO/FIN and n = 203 TAD/FIN). Results show that men receiving the TAD/FIN therapy had significantly improved IIEF-EF scores at all three times as well. The LS mean changes in IEFF-EF scores were 3.7, 4.7, and 4.7 after 4, 12, and 26 weeks of TAD/FIN, respectively. Overall, the LSTDs between TAD/FIN and PBO/FIN at the three respective time points from baseline were 4.9, 4.1, and 4.7 (p < 0.001). The difference in EF remained essentially the same throughout the duration of the trial, indicating the significant benefit of tadalafil [Elkelany et al. 2015]. Another interesting finding from this study was observed in a subgroup of men who had no prior ED. Despite not having any pervious dysfunction the TAD/FIN therapy improved sexual desire, EF, orgasmic function, and overall satisfaction with intercourse. It is believed that these effects are a result of tadalafil stimulating the NO cascade through the upregulation of cGMP, leading to increased blood flow and the neural response to male genitalia [Elkelany et al. 2015]. Several other secondary outcomes were measured as well, including IPSS (storage and voiding subscore), IPSS QOL, erectile function domain of IIEF-EF, Patient Global Impression of Improvement (PGII) and clinician Global Impression of Improvement (CGII). Interestingly, all five key secondary efficacy outcomes were statistically significantly improved in the TAD/FIN group as well. Overall, this study made conclusive findings that daily 5 mg tadalafil coadministered with 5 mg finasteride in men with LUTS and ED secondary to BPH resulted in significant and early LUTS improvement compared with monotherapy alone [Casabé et al. 2014].

A subsequent study looking at the same study participants was designed to evaluate treatment satisfaction and clinically meaningful symptom improvement [Roehrborn et al. 2015]. As described above, the RCT had a 6-month treatment period and men were randomized into either the TAD/FIN combinatorial therapy group or PBO/FIN monotherapy group. In this study, post hoc analysis was performed of the minimal clinically important differences (MCID) in IPSS and prespecified van Elteren analysis was done for treatment satisfaction based on the Treatment Satisfaction Scale-Benign Prostatic Hyperplasia (TSS-BPH). According to past literature and the American Urological Association, there are two ways to define the MCID: a decrease of at least three points in total IPSS or at least a 25% decrease in total IPSS [Barry et al. 1995; McVary et al. 2010]. Both of these definitions were considered when performing the post hoc analysis of the MCID in IPSS. At weeks 4, 12, and 26, the proportion of TAD/FIN responders was 57.0%, 68.8%, and 71.4%, respectively, and the proportion of PBO/FIN responders was 47.9%, 60.7%, and 70.2% when defining responders as those who displayed at least a three-point decrease in total IPSS. Alternatively, when responders were defined as those who displayed at least a 25% decrease in total IPSS, the proportion of TAD/FIN responders was 44.8%, 55.5%, and 62.0% for the three time points and 32.9%, 51.9%, and 58.3% for the PBO/FIN group. Odds ratio of IPSS decrease of at least three points was statistically significant in favor of TAD/FIN at week 4 and week 12 [OR 1.45, 95% confidence interval (CI) 1.07–1.97 and OR 1.48, 95% CI 1.07–2.05, respectively], but were not significantly different at week 26 (OR 1.14, 95% CI 0.81–1.61) [Roehrborn et al. 2015].

In this study treatment satisfaction was another primary outcome and was measured through the TSS-BPH, which is a 13-item questionnaire split into three sections: satisfaction with efficacy, dosing and side effects, with low scores representing a higher overall patient satisfaction [Black et al. 2009; Hareendran and Abraham, 2005]. TSS-BPH data are only available from the final time point in this study, which presents a significant limitation for this study. Nonetheless, data from the 6-month end point demonstrate that patient satisfaction is significantly higher in the TAD/FIN group compared with the PBO/FIN group. This higher satisfaction is apparent in the total TSS-BPH scores (mean 2.0 TAD/FIN versus 2.1 PBO/FIN, p = 0.031) and also the efficacy subscore (mean 33.7 TAD/FIN versus 36.6 PBO/FIN, p = 0.025), but not in the dosing or side effects subscores. Combined, data from the post hoc analysis and prespecified van Elteren analysis support the superiority of TAD/FIN combinatorial therapy over finasteride monotherapy. Men taking daily 5 mg tadalafil coadministered with 5 mg finasteride were more likely to achieve a MCID in IPSS and to have higher patient perceived satisfaction compared with men taking just finasteride. These data further support the utility of coadministration of tadalafil for early symptom improvement in men starting treatment with a 5-ARI [Roehrborn et al. 2015].

Past evidence supports a benefit of the α-blocker and a 5-ARI combinatorial therapy in treating and improving BPH LUTS. More recent studies suggest that combining PDE-5 inhibitors with 5-ARIs offers a novel therapy capable of producing positive treatment results comparable in efficacy [Casabé et al. 2014; Roehrborn et al. 2015; Elkelany et al. 2015]. From past clinical evidence it seems like men with prostatic volumes greater than 30 ml along with those who have moderate to severe urinary symptoms will benefit most from this new therapy [Elkelany et al. 2015]. Furthermore, this therapy is ideal in men who want to avoid surgical intervention and the negative sexual side effects such as retrograde ejaculation commonly observed in those on α-blocker therapy. Unlike the α-blocker and a 5-ARI combinatorial therapy, it seems like tadalafil coadministered with finasteride offers a novel secondary benefit in its ability to improve EF without causing sexual side effects [Elkelany et al. 2015]. Thus, this therapy is attractive for men who have existing ED prior to treatment course. Lastly, although 5-ARI therapy does prevent the progression of BPH and reduce the need for surgical intervention, often it takes between 6 and 12 months before these positive changes are observed. Combining tadalafil in this treatment regime has been shown to speed up the onset of action and thus offers another benefit to this novel combinatorial therapy [Elkelany et al. 2015].

Safety and tolerability

The safety and tolerability profile of tadalafil and finasteride have previously been evaluated in multiple studies investigating these drugs as monotherapeutic agents. In a 12-week single-blind RCT in which men were randomly assigned to either 5 mg of tadalafil or placebo, AEs were compared between the two groups [McVary et al. 2007b]. Among the 280 men in the study, the most common treatment-emergent adverse events (TEAEs) were increased erection (5.1% tadalafil versus 1.4% placebo), dyspepsia (4.3% tadalafil versus 0% placebo), back pain (3.6% tadalafil versus 0% placebo) and headache (2.9% tadalafil versus 0.7% placebo). Despite these AEs there were no reports of priapism and between the two groups there were no significant changes in PSA or other relevant laboratory values. Furthermore, the only serious adverse event (SAE) occurred in the placebo control group and there were no clinically relevant changes in vital signs or reports of AUR. Overall, the proportion of patients who discontinued based on TEAEs was similar between the two groups: 3.6% in the tadalafil group compared with 1.4% in the placebo group [McVary et al. 2007b]. Similar results were also replicated in a larger RCT investigating multiple dosing levels of tadalafil [Roehrborn et al. 2008]. In this study the major TEAEs were also back pain (3.4% tadalafil versus 2.8% placebo), headache (3.4% tadalafil versus 2.8% placebo), dyspepsia (3.3% tadalafil versus 0% placebo), and myalgia (2.1% tadalafil versus 0% placebo). All TEAEs were infrequent in participants and rarely did they lead to discontinuation in either group. Among the pooled tadalafil groups, 4.8% discontinued based on TEAEs, while in the placebo group the proportion was 2.4%. Although discontinuation was more likely in the treatment branches of this trial, from a safety perspective all doses of tadalafil were well tolerated. Furthermore, although the incidence of patients with one or more TEAEs increased with increasing tadalafil doses, no clear relationship was observed between the tadalafil dose and individual AEs. In addition, no clinically relevant changes in laboratory parameters, vital signs, mean PSA or mean post void residual (PVR) urine were observed. Interestingly, the proportion of SAEs was higher in the placebo group, suggesting that they are not attributed to the tadalafil treatment [Roehrborn et al. 2008]. Furthermore, according to manufacture guidelines, individuals with angina, renal or hepatic impairment and those who are taking α-blockers, antihypertensives or potent CYP3A4 inhibitors should not take tadalafil as it could worsen or potentiate symptoms and effects [Elkelany et al. 2015]. It is also suggested that tadalafil is contraindicated in men taking nitrates for cardiac disease and in men who have a history of serious hypersensitivity reactions to tadalafil [Elkelany et al. 2015]

Similar studies investigating the efficacy of finasteride monotherapy provide insight into its safety and tolerability profile as well. The most common TEAEs with finasteride therapy are all sexually related and included impotence (2.1%), decreased libido (1%), and gynecomastia (0.4%) [Wilde and Goa, 1999]. In a large RCT with over 7000 participants comparing finasteride with placebo over 2 years, AEs related to sexual dysfunction were significantly greater in the finasteride group (2.1–19%) compared with the placebo group (0.6–10%). Fortunately, most AEs were mild and the proportion of discontinuations due to AEs was similar in both groups in this study. Interestingly, neither the dose of finasteride nor the length of therapy were contributing factors in the incidence of these sexually related AEs [Wilde and Goa, 1999]. Other large multicenter, randomized, placebo-controlled trials comparing different doses of finasteride have also been completed to evaluate the drug’s safety in men with BPH. Patients in one study were randomized to either 1 mg of finasteride, 5 mg of finasteride, or placebo for 12 months. Following the 12 months patients were enrolled in a 2-year open extension study and received 5 mg of finasteride regardless of their original therapy [Stoner, 1994]. The group receiving 5 mg of finasteride from baseline was the major focus given that this is the approved therapeutic dosage for men with BPH. Among the 543 men who started in the 5 mg finasteride group, after 3 years, 297 (55%) had completed the necessary data collection to be considered in the analysis. Out of the remaining 246 participants, 68 (12%) lacked sufficient data and 178 patients (33%) dropped out of the study prior to reaching the 3-year time mark. Most of these dropouts were attributed to loss of follow-up or withdrawn consent as opposed to a result of clinical or sexual TEAEs [Stoner, 1994]. Among those who could be analyzed, results show that finasteride has a strong safety and tolerability profile. Across the 36-month time period of this study there was no increase in the rate at which AEs occurred. In fact, as the duration of the treatment continued, new drug-related sexual AEs actually decreased and 60% of men who had a sexual AE found that it was resolved with continued treatment. The most common drug-related AE was impotence, which occurred in 3.7%, 3.2%, and 2.1% of finasteride-treated participants after 1–3 years, respectively (1.1% placebo). Other drug-related AEs include decreased libido (3.3% 1 year versus 1.6% placebo) and decreased ejaculate volume (2.6% 1 year versus 0.9% placebo). Although some sexual drug-related AEs were more likely in participants taking 5 mg of finasteride compared with placebo, there were no significant differences in the occurrence of most clinical AEs over the 36 months. Furthermore, there were no significant differences in the percentage of patients who reported SAEs over the course of the study when comparing placebo (9.4%) with 5 mg finasteride (6.8%). For the vast majority of these SAEs they were considered nondrug related, further highlighting the safety of therapeutic doses of finasteride [Stoner, 1994]. As stated previously there is still some uncertainty as to whether finasteride increases an individual’s risk of developing high-grade prostatic cancer. Men aged 55 and over with a normal DRE and PSA up to 3.0 ng/ml at baseline taking finasteride 5 mg/day in the 7-year PCPT had an increased risk of Gleason score 8–10 prostate cancer (finasteride 1.8% versus placebo 1.1%). The impact of these results has not yet been established and it is unclear whether the reduction in prostate volume caused by finasteride or study-related factors played a role in them. One follow-up study suggests that the effects of finasteride on prostate volume and selective inhibition of low-grade cancer may have contributed to the increase in high-grade cancers with finasteride in the PCPT [Lucia et al. 2007].

In the latest RCTs exploring finasteride and tadalafil as combinatorial agents, a high safety profile has been observed [Casabé et al. 2014; Roehrborn et al. 2015]. In these trials participants were randomized to two different groups: once daily placebo/5 mg finasteride (n = 350) (PBO/FIN) and once daily 5 mg tadalafil/5 mg finasteride (n = 346) (TAD/FIN) for 26 weeks. Due to the similarities in the metabolism of finasteride and tadalafil through CYP3A4 isoenzymes researchers did not anticipate there would be any major interaction between these two drugs. Past evidence suggests that neither agent can inhibit or induce CYP3A4 activity, allowing for these two drugs to be combined in a therapy without much concern. Results from the study reinforce these findings and show that the incidence and severity of AEs was not increased or worsened in the TAD/FIN group. Overall the safety profile of TAD/FIN therapy did not deviate from the safety profile established in monotherapeutic trials described previously. Interestingly, the incidence of sexually related AEs such as impotence, decreased libido, and ejaculatory abnormalities were less common in the TAD/FIN group compared with the PBO/FIN group [Casabé et al. 2014]. These AEs are commonly reported among men prescribed finasteride and were shown to be higher in the PBO/FIN group. Interestingly, although the incidence of these AEs were elevated in the PBO/FIN group, the proportion in the PBO/FIN group was lower than that typically reported for 5-ARI monotherapy. Researchers attributed these finding to patient bias, speculating that the fact participants knew they had a 50% chance of receiving a drug known to improve sexual function reduced the overall reporting of these types of AEs [Casabé et al. 2014]. During the 26-week study there were a total of two deaths. One man passed away from metastatic pancreatic carcinoma 65 days after randomization to the TAD/FIN group, while the other man was in the PBO/FIN group and died from a cerebrovascular incident 148 days after randomization. Neither of these deaths were believed to have any relation to the drug therapy or the study procedure. As expected, classical AEs of tadalafil such as back pain, headache, dyspepsia, and flu-like symptoms were reported in 1.7%, 3.4%, 0.6%, and 2.3% of men on PBO/FIN versus 4.6%, 3.5%, 2.3%, and 2.3% of men on combination therapy. Although the incidence of TEAEs was higher in the TAD/FIN group (31.3%) compared with the PBO/FIN group (27.1%), this difference was not statistically significant. Furthermore, only a small proportion of these TEAEs were characterized as being related to the treatment itself (PBO/FIN 5.4% versus TAD/FIN 8.7%). The number of SAEs and discontinuations due to AEs was also low in both groups and not significantly different between either of the treatment groups. Fortunately, there was significant difference in the occurrence of treatment-related sexual AEs in favor of the TAD/FIN group, suggestive of an additional benefit of this combinatorial therapy [Casabé et al. 2014].

Conclusion

A variety of treatment options exist for those with BPH; however, pharmacotherapies are desirable due to their minimal invasiveness. With three classes of drugs available for the treatment of BPH, much of the most recent research has been towards finding new combinatorial therapies that improve symptom relief. 5-ARI/α-blocker coadministration has long since been accepted as one such combinatorial therapy for those with BPH. Although this therapy does offer additional LUTS relief compared with monotherapies, it also increases the incidence of sexually related AEs. Due to this limitation, the search for other combinatorial therapies effective in treating BPH has continued. Initial studies investigating 5-ARI/PDE-5 inhibitor coadministration show that the combination of finasteride and tadalafil is a safe and effective alternative therapy. Tadalafil and finasteride together can relieve LUTS in men with BPH while also help protect individuals from the negative sexually related AEs reported by those on 5-ARI/α-blocker therapy.