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Evolution of phosphodiesterase type 5 inhibitors in treatment of erectile dysfunction in Taiwan
Urological Science xxx (2016) 1e5
Contents lists available at ScienceDirect
Urological Science journal homepage: www.urol-sci.com
Review article
Evolution of phosphodiesterase type 5 inhibitors in treatment of erectile dysfunction in Taiwan Bang-Ping Jiann a, b, * a b
Division of Basic Medical Research, Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan School of Medicine, National Yang-Ming University, Taipei, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 January 2016 Received in revised form 12 April 2016 Accepted 13 April 2016 Available online xxx
Erectile dysfunction (ED) is a prevalent form of male sexual dysfunction. Phosphodiesterase type 5 (PDE5) inhibitor is the first-line treatment for ED. Numerous well-designed and -conducted clinical trials and postmarketing studies have established the safety and efficacy of PDE5 inhibitors for the treatment of ED. Ever since the first approval of sildenafil in 1998, PDE5 inhibitors have had several advances in their clinical use. More new agents with different pharmacokinetic profiles and new formulations were marketed. Conventional on-demand administration expanded to daily dosing. These advances provide more flexibility in clinical treatment of ED for patients and physicians. Moreover, clinical indications of PDE5 inhibitors extend from treatment of ED to pulmonary arterial hypertension and signs and symptoms of benign prostatic hyperplasia because of the distribution of PDE5 enzyme in human organs and tissues. The evolution of PDE5 inhibitors heralds a remarkable medical history from bench to clinical practice. Copyright © 2016, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: erectile dysfunction PDE5 inhibitor sildenafil tadalafil vardenafil
1. Introduction
2. Serendipity: From angina to erectile dysfunction
The phosphodiesterase (PDE) system had been identified for many years but was not initially considered to play a significant physiological role in humans. The system includes 11 families with > 50 isoforms and is widely distributed in human organs and tissues.1 PDEs catalyze breakdown of cyclic GMP or cyclic AMP, so-called second messengers, which in turn are converted to biologically inactive monophosphates, resulting in termination of their physiological functions. PDE type 5 was first discovered by Francis and Corbin2 in 1980 and is enriched in the corpus cavernosum compared with other PDE enzymes. PDE5 enzyme is a homodimer containing two identical subunits that each consists of regulatory and catalytic domains (Figure 1). The catalytic domain is the direct target of PDE5 inhibitors. The regulatory domain contains allosteric cGMP-binding sites and a phosphorylation site for negative feedback regulation of the enzyme.3
The discovery of PDE5 inhibitors for treatment of erectile dysfunction (ED) is a remarkable case of serendipity. Before the advent of PDE5 inhibitors, treatment choices for ED were limited to penile implant and intracavernosal injection. The invasive nature and fear of injection prevented them from widespread acceptance by patients and physicians. Only a small portion of ED patients ever benefited from such treatments. In 1989, compound UK-92,480, now better known as sildenafil citrate, was first synthesized and tested in Pfizer's laboratories.4 Preliminary data showed that inhibiting PDE5 might produce beneficial effects of decreased vascular resistance and reduced platelet aggregation. Clinical studies on sildenafil citrate 50 mg, three times daily, as an antiangina agent began in 1991 in England but the clinical effects were mild. The untoward side effect of penile erection hinted to scientists that PDE5 and cGMP might play a role in penile erection and the potential of sildenafil as a treatment for ED. Occupation of the catalytic domain by PDE5 inhibitor, a competitive inhibitor, blocks the access of cGMP and its breakdown, which increases the concentration of cGMP in tissues. The Ignarro group reported that penile erection was mediated through elevation of NO-induced cGMP in corpus cavernosum smooth muscle of rabbits in 1990.5 Subsequent research provided insights into the biological and
* Division of Basic Medical Research, Department of Medical Education and Research, Kaohsiung Veterans General Hospital, 386, Tachung 1st Road, Kaohsiung 81362, Taiwan. E-mail addresses: [email protected], [email protected].
http://dx.doi.org/10.1016/j.urols.2016.04.003 1879-5226/Copyright © 2016, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Jiann B-P, Evolution of phosphodiesterase type 5 inhibitors in treatment of erectile dysfunction in Taiwan, Urological Science (2016), http://dx.doi.org/10.1016/j.urols.2016.04.003
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B.-P. Jiann / Urological Science xxx (2016) 1e5
for efficacy and safety of PDE5 inhibitors for the treatment of ED are attributed to sildenafil, tadalafil, and vardenafil. Numerous wellconducted randomized placebo-control trials and postmarketing studies have established their safety and efficacy in the treatment of ED.9,11,12 Oral PDE5 inhibitors are generally recommended for first-line therapy unless they have contraindications for clinical use. A tremendous growth of utilization data of PDE5 inhibitors in global and Taiwan markets was reported from 1999 to 2011.13 The success of oral pharmacotherapy for ED culminated in the introduction of more agents, advent of new formulations and routes of administration, and new clinical indications for PDE5 inhibitors in the past decade (Table 1). PDE5 inhibitors can be administered orally at concentrations sufficient to inhibit PDE5 with minimal serious side effects related to inhibition of other PDEs or non-PDE targets. The most commonly reported treatment-emergent adverse events include headache, flushing, and gastrointestinal upset that are related to the distribution of PDE enzyme, and are transient and mild in severity.9 However, rare serious toxicity has been reported in association with PDE5 inhibitor use, including hearing loss, nonarteritic anterior ischemic optic neuropathy, and priapism.14 A critical analysis and review of the literature demonstrates no conclusive evidence to indicate a direct causeeeffect relationship between PDE5 inhibitor use and vision-threatening ocular events.15 Likewise, no causal link could be established between sildenafil and cardiovascular events or any new safety risk relating to cardiovascular events and those rare toxicities.10 4. New PDE5 inhibitors
Figure 1. Structure of PDE5 enzyme shows two identical submits and each contains a catalytic and a regulatory domain. PDE5 inhibitors target the catalytic domain. The regular domain in the amino-terminal protein contains a phosphorylation site and two allosteric cGMP-binding sites (a and b). PDE5 ¼ phosphodiesterase type 5; cGMP ¼ cyclic guanosine manuscript; p ¼ phosphate; S ¼ serine-102.
pharmacological roles of NO, cGMP, and PDE5 in the regulation of vascular smooth muscle relaxation and vasodilation, and penile erection. Accumulation of cGMP in smooth muscle cells of the penile corpus cavernosum after taking a PDE5 inhibitor results in improvement of erectile rigidity and helps management in men with erectile impairment. The first pivotal study of sildenafil for ED treatment consisted of a two-phase crossover study.6 In the first phase, patients were randomized to sildenafil 10 mg, 25 mg, or 50 mg or placebo, and in the second phase, patients were randomized to sildenafil 25 mg or placebo for 7 days. Compared with placebo, taking sildenafil with sexual stimulation significantly improved penile erection in men with ED as monitored by nocturnal penile erection device.6 A pivotal Phase III study of sildenafil was published in 1998,7 in which the efficacy was assessed by a validated 15-item self-reported questionnaire, the International Index of Erectile Function (IIEF).8 Sildenafil (Viagra; Pfizer, New York, NY, USA) was the first PDE5 inhibitor approved for treatment of ED in the US in 1998 and Taiwan in 1999. Tadalafil (Cialis; Lilly ICOS, Indiana, IN, USA) and vardenafil (Levitra; Bayer AG, Leverkusen, Germany) were approved in Taiwan in 2003. Pharmacotherapy with PDE5 inhibitors has the advantages of easy administration and good effectiveness with minimal side effects, which brought a revolutionary change in the treatment of ED.9 3. Safety and efficacy of PDE5 inhibitors PDE5 inhibitors are probably the best studied in well-designed clinical trials on the planet.10 Most currently available evidence
The success of the first generation of PDE5 inhibitors has stimulated the development and marketing of more new PDE5 inhibitors (Table 1) that provide greater flexibility for physicians and patients in clinical use. Udenafil16 (Zydena; Dong-A Pharmaceutical Co., Seoul, Korea) has a relatively rapid onset [time to maximum concentration (Tmax) ¼ 1e1.5 hours] and a long duration of action (T1/2 ¼ 11e13 hours; Table 2), and can be used on demand or once daily.17 To date, udenafil is approved only in Korea, Russia, and the Philippines. Avanafil (Stendra or Spedra; Vivus, Mountain View, CA, USA) has the advantage of rapid onset (Tmax 35 minutes) and a short half-life (< 1.5 hours)18 compared with other PDE5 inhibitors. Avanafil was approved by the United States Federal Drug Administration (FDA) in 2012 and by the European Medicines Agency in 2013. Mirodenafil (SK Chemicals Life Science, Seoul, South Korea) is characterized by its selectivity toward PDE5 being 10-fold higher than that of sildenafil, whereas its inhibitory effects on other PDEs were much lower than those of sildenafil in preclinical studies.19 Mirodenafil was approved in Korea in 2007.20 5. New formulation The oral route of administration is the most convenient and popular for most therapeutic agents. Conventional PDE5 inhibitors are produced as solid film-coated tablets and have to be swallowed with water. Oral dispersible tablets (ODTs) provide a novel and an attractive formulation, dissolving or disintegrating rapidly in the oral cavity. Compared to conventional film-coated tablets, ODT formulation has several advantages, including rapid onset, easier administration (without water), bypassing the gastrointestinal tract and hepatic portal systems, and better patient compliance.21 ODTs have a palatable flavor because of oral dissolving, avoiding a bitter taste and a connection with taking a pill for sex. Levitra ODT (10 mg) was the first PDE5 inhibitor introduced in ODT formulation with a minty taste in 2011. A pharmacokinetic study demonstrated that taking vardenafil ODT without water can
Please cite this article in press as: Jiann B-P, Evolution of phosphodiesterase type 5 inhibitors in treatment of erectile dysfunction in Taiwan, Urological Science (2016), http://dx.doi.org/10.1016/j.urols.2016.04.003
B.-P. Jiann / Urological Science xxx (2016) 1e5 Table 1 Advances in the phosphodiesterase type 5 inhibitors in clinical use. Variables
Remarks (Agents approved)
Agents
1st generation: sildenafil, tadalafil, & vardenafil 2nd generation: udenafil, avanafil, & mirodenafil Traditional: film-coated (all agents) New: orodispersible tablet (vardenafil, sildenafil, & mirodenafil) Traditional: on demand (all agents) New: daily dosing (tadalafil) 1. Erectile dysfunction (all the agents) 2. Pulmonary artery hypertension (sildenafil & tadalafil) 3. Lower urinary tract symptoms secondary to benign prostatic hyperplasia (tadalafil)
Formulation Dosing Indications
Table 2 Pharmacokinetics of the phosphodiesterase type 5 inhibitors. Agents
Cmax ng/mL
Tmax (h)
T1/2 (h)
Sildenafil 100 mg Tadalafil 20 mg Vardenafil 20 mg Udenafil 100 mg Avanafil 100 mg Mirodenafil 100 mg
450 378 20.9 416.2 871 373.4
0.8 2 0.7e0.8 1e1.5 0.5e1.5 1.25
3e5 17.5 4e5 11e13 <1.5 2.5
Cmax ¼ maximum plasma concentration; Tmax time to reach Cmax; T1/2 ¼ half-life.
increase bioavailability by 21e44% in the area under the plasma concentrationetime curve, compared with film-coated tablets in men with ED.22 Integrated analyses of two pivotal trials of Levitra ODT demonstrated its effectiveness and safety in men with ED and its time to onset of action was comparable to that of film-coated tablets.23,24 Sildenafil ODT (50 mg) with a lemon flavor was introduced in Taiwan in 2015. Pharmacokinetic studies showed no significant difference between sildenafil ODTs and film-coated tablets.25,26 The study also showed that a high-fat meal reduced absorption of ODT and therefore sildenafil ODT should be taken on an empty stomach.26 However, no study has been conducted to prove whether ODT formulation is preferred over conventional film-coated formulation in clinical practice. 6. Route of administration Sildenafil was the first drug designed for use only if necessary (on demand), although initially it was designed to be taken three times daily. ED patients have to take sildenafil or vardenafil 1 hour before and tadalafil 2 hours before sexual activity, considering the onset and Tmax (Table 2). The therapeutic window may last for 12 hours for 100 mg sildenafil,27 10 hours for 20 mg vardenafil,28 and 36 hours for 20 mg tadalafil,29 which is approximately two times their half-life (Table 2). Taking a pill before sexual activity does not necessarily represent successful sexual intercourse. Sexual activity may be influenced by the behavioral complexity of sexual intimacy, such as the communication and coordination around the frequency, timing and initiation of sexual activity.30,31 A large population survey in Eastern countries revealed that 50% of men did not want to plan their sexual activity.32
3
A longer duration of therapeutic window allows more spontaneity for sex and more time to look for the optimal moment for sex than a shorter therapeutic window. Tadalafil has the longest halflife (17.5 hours) among the PDE5 inhibitors. The first study of daily dosing of tadalafil 10 mg or 20 mg was conducted to salvage previously unresponsive to on-demand tadalafil and 60% of patients converted to responders.33 A pharmacokinetic study showed that at the simulated steady state, tadalafil 5 mg once daily provided plasma concentrations > 55 ng/mL, and ~90% enzyme inhibition in vitro,34 which is similar to those observed 24 hours after tadalafil 20 mg two or three times weekly.35 An integrated analysis of data from six randomized, placebo-control trials showed that improvement rate in mild, moderate, and severe ED after taking tadalafil 5 mg once daily was 74.8%, 63.1%, and 44.5%, respectively.36 The response rate in men with ED showed no significant difference between tadalafil on demand and once daily; however, a lower incidence of treatment-emergent adverse events ( 4%) was reported for tadalafil once daily because of a lower peak plasma concentration than on demand.37,38 The differences in clinical effect of PDE5 inhibitors administered on demand or daily for the treatment of ED are compared in Table 3.
7. New clinical indications According to the classification of the World Health Organization, pulmonary hypertension has five classes: idiopathic pulmonary arterial hypertension (PAH) and the remaining four groups with different etiologies. Patients with PAH have two important features in the pulmonary vasculature: increased expression of the vasoconstrictor PDE5 and decreased production of the vasodilator NO.39 An illustrative trial (SUPER-1 trial)40 and an open-label 3-year extension trial (SUPER-2 trial)41 established the efficacy of sildenafil in the treatment of PAH. Compared with placebo, sildenafil improved 6-minute walking distance, mean pulmonary artery pressure, and functional class in a dose-dependent fashion. The FDArecommended dose for sildenafil for treatment of PAH is 20 mg three times daily. Tadalafil also demonstrated its clinical improvement in PAH in the PHIRST-142 and -243 trials. The FDA-recommended dose for treatment of PAH is tadalafil 40 mg daily. Vardenafil is not approved by the FDA for the treatment of PAH, although clinical improvement was also demonstrated in the trial.44 Altitude sickness consists of three syndromes: acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema (HAPE). HAPE usually occurs at altitudes > 3000 m in rapidly ascending nonacclimatized individuals within the first 2e5 days after arrival.45 The prevalence of HAPE depends on the degree of susceptibility, rate of ascent, and final altitude. Rapid ascent is the most important and modifiable risk factor. HAPE is the leading cause of death from altitude sickness, but can be prevented by careful ascent and reversed with early recognition and treatment. Placebo-controlled trials confirmed that taking sildenafil or tadalafil can significantly reduce the incidence of HAPE.46,47 PDE5 inhibitors (sildenafil and tadalafil) have been shown to be effective and safe in the treatment and prevention of HAPE.48
Table 3 Differences in clinical effect of phosphodiesterase type 5 inhibitors administered on demand or daily for treatment of erectile dysfunction. Variables
On-demand administration
Once daily administration
Time frame for sex Sexual frequency Incidence of treatment-emergent adverse effects Peak plasma concentration of agent Treatment expenditure Beneficial effects on lower urinary tract symptoms
Yes For all sexual frequencies Higher Adequate Relatively lower Intermittent
Spontaneity, no time frame Appropriate for men with high sexual frequency Lower May not be enough for men who are considered difficult to treat Higher Constant
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ED and lower urinary tract symptoms (LUTSs) secondary to benign prostatic hyperplasia (BPH) are common medical diseases in men older than 50 years. Epidemiological studies suggest there is a strong correlation between both of them.49 mRNA expression for PDE5 has been demonstrated in rat lower urinary tract tissue.50 Sildenafil, tadalafil, and vardenafil dose-dependently reduced contraction of isolated bladder and urethral and prostate strips in animal studies,50 and clinical studies showed improvement in LUTSs.51 Nevertheless, only tadalafil 5 mg once daily is approved for the treatment of LUTSs secondary to BPH with or without ED. An integrated analysis of pooled data from four randomized, placebocontrolled tadalafil clinical studies demonstrated that significant improvement in ED (assessed by the IIEF) and LUTSs [assessed by the International Prostate Symptom Score (IPSS)] were confirmed regardless of baseline severity and improvements in the total IPSS and the IIEF-Erectile Function domain score were weakly correlated.52 Combined use of PDE5 inhibitor and a-blockers provided additive favorable effects in symptomatic relief compared with PDE5 inhibitor monotherapy.53 Long-term results for combination of tadalafil with a-blockers for the treatment of ED and BPH in men is still lacking. Prescribing daily PDE5 inhibitors for the treatment of LUTSs secondary to BPH faces a major challenge of costeffectiveness compared with a-blockers in clinical practice. 8. Conclusions PDE5 inhibitor is the most popular form for treatment of ED. More new PDE5 inhibitors, new preparation methods of agents and daily dosing provide more flexibility in clinical treatment for ED patients and physicians. Moreover, the clinical indications of PDE5 inhibitors have extended from ED to PAH and LUTSs secondary to BPH. Possible future indications for versatile PDE5 inhibitors are still developing that may provide new solutions for diseases in the future.
Conflict of interest Dr. Jiann gets grant and research support from Eli-Lilly and Pfizer Pharmaceuticals. Dr. Jiann is also an invited speaker for Pfizer, Eli-Lilly, Bayer, Menarini, and Orient Pharmaceuticals.
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Urological Science journal homepage: www.urol-sci.com
Review article
Evolution of phosphodiesterase type 5 inhibitors in treatment of erectile dysfunction in Taiwan Bang-Ping Jiann a, b, * a b
Division of Basic Medical Research, Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan School of Medicine, National Yang-Ming University, Taipei, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 January 2016 Received in revised form 12 April 2016 Accepted 13 April 2016 Available online xxx
Erectile dysfunction (ED) is a prevalent form of male sexual dysfunction. Phosphodiesterase type 5 (PDE5) inhibitor is the first-line treatment for ED. Numerous well-designed and -conducted clinical trials and postmarketing studies have established the safety and efficacy of PDE5 inhibitors for the treatment of ED. Ever since the first approval of sildenafil in 1998, PDE5 inhibitors have had several advances in their clinical use. More new agents with different pharmacokinetic profiles and new formulations were marketed. Conventional on-demand administration expanded to daily dosing. These advances provide more flexibility in clinical treatment of ED for patients and physicians. Moreover, clinical indications of PDE5 inhibitors extend from treatment of ED to pulmonary arterial hypertension and signs and symptoms of benign prostatic hyperplasia because of the distribution of PDE5 enzyme in human organs and tissues. The evolution of PDE5 inhibitors heralds a remarkable medical history from bench to clinical practice. Copyright © 2016, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: erectile dysfunction PDE5 inhibitor sildenafil tadalafil vardenafil
1. Introduction
2. Serendipity: From angina to erectile dysfunction
The phosphodiesterase (PDE) system had been identified for many years but was not initially considered to play a significant physiological role in humans. The system includes 11 families with > 50 isoforms and is widely distributed in human organs and tissues.1 PDEs catalyze breakdown of cyclic GMP or cyclic AMP, so-called second messengers, which in turn are converted to biologically inactive monophosphates, resulting in termination of their physiological functions. PDE type 5 was first discovered by Francis and Corbin2 in 1980 and is enriched in the corpus cavernosum compared with other PDE enzymes. PDE5 enzyme is a homodimer containing two identical subunits that each consists of regulatory and catalytic domains (Figure 1). The catalytic domain is the direct target of PDE5 inhibitors. The regulatory domain contains allosteric cGMP-binding sites and a phosphorylation site for negative feedback regulation of the enzyme.3
The discovery of PDE5 inhibitors for treatment of erectile dysfunction (ED) is a remarkable case of serendipity. Before the advent of PDE5 inhibitors, treatment choices for ED were limited to penile implant and intracavernosal injection. The invasive nature and fear of injection prevented them from widespread acceptance by patients and physicians. Only a small portion of ED patients ever benefited from such treatments. In 1989, compound UK-92,480, now better known as sildenafil citrate, was first synthesized and tested in Pfizer's laboratories.4 Preliminary data showed that inhibiting PDE5 might produce beneficial effects of decreased vascular resistance and reduced platelet aggregation. Clinical studies on sildenafil citrate 50 mg, three times daily, as an antiangina agent began in 1991 in England but the clinical effects were mild. The untoward side effect of penile erection hinted to scientists that PDE5 and cGMP might play a role in penile erection and the potential of sildenafil as a treatment for ED. Occupation of the catalytic domain by PDE5 inhibitor, a competitive inhibitor, blocks the access of cGMP and its breakdown, which increases the concentration of cGMP in tissues. The Ignarro group reported that penile erection was mediated through elevation of NO-induced cGMP in corpus cavernosum smooth muscle of rabbits in 1990.5 Subsequent research provided insights into the biological and
* Division of Basic Medical Research, Department of Medical Education and Research, Kaohsiung Veterans General Hospital, 386, Tachung 1st Road, Kaohsiung 81362, Taiwan. E-mail addresses: [email protected], [email protected].
http://dx.doi.org/10.1016/j.urols.2016.04.003 1879-5226/Copyright © 2016, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Jiann B-P, Evolution of phosphodiesterase type 5 inhibitors in treatment of erectile dysfunction in Taiwan, Urological Science (2016), http://dx.doi.org/10.1016/j.urols.2016.04.003
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for efficacy and safety of PDE5 inhibitors for the treatment of ED are attributed to sildenafil, tadalafil, and vardenafil. Numerous wellconducted randomized placebo-control trials and postmarketing studies have established their safety and efficacy in the treatment of ED.9,11,12 Oral PDE5 inhibitors are generally recommended for first-line therapy unless they have contraindications for clinical use. A tremendous growth of utilization data of PDE5 inhibitors in global and Taiwan markets was reported from 1999 to 2011.13 The success of oral pharmacotherapy for ED culminated in the introduction of more agents, advent of new formulations and routes of administration, and new clinical indications for PDE5 inhibitors in the past decade (Table 1). PDE5 inhibitors can be administered orally at concentrations sufficient to inhibit PDE5 with minimal serious side effects related to inhibition of other PDEs or non-PDE targets. The most commonly reported treatment-emergent adverse events include headache, flushing, and gastrointestinal upset that are related to the distribution of PDE enzyme, and are transient and mild in severity.9 However, rare serious toxicity has been reported in association with PDE5 inhibitor use, including hearing loss, nonarteritic anterior ischemic optic neuropathy, and priapism.14 A critical analysis and review of the literature demonstrates no conclusive evidence to indicate a direct causeeeffect relationship between PDE5 inhibitor use and vision-threatening ocular events.15 Likewise, no causal link could be established between sildenafil and cardiovascular events or any new safety risk relating to cardiovascular events and those rare toxicities.10 4. New PDE5 inhibitors
Figure 1. Structure of PDE5 enzyme shows two identical submits and each contains a catalytic and a regulatory domain. PDE5 inhibitors target the catalytic domain. The regular domain in the amino-terminal protein contains a phosphorylation site and two allosteric cGMP-binding sites (a and b). PDE5 ¼ phosphodiesterase type 5; cGMP ¼ cyclic guanosine manuscript; p ¼ phosphate; S ¼ serine-102.
pharmacological roles of NO, cGMP, and PDE5 in the regulation of vascular smooth muscle relaxation and vasodilation, and penile erection. Accumulation of cGMP in smooth muscle cells of the penile corpus cavernosum after taking a PDE5 inhibitor results in improvement of erectile rigidity and helps management in men with erectile impairment. The first pivotal study of sildenafil for ED treatment consisted of a two-phase crossover study.6 In the first phase, patients were randomized to sildenafil 10 mg, 25 mg, or 50 mg or placebo, and in the second phase, patients were randomized to sildenafil 25 mg or placebo for 7 days. Compared with placebo, taking sildenafil with sexual stimulation significantly improved penile erection in men with ED as monitored by nocturnal penile erection device.6 A pivotal Phase III study of sildenafil was published in 1998,7 in which the efficacy was assessed by a validated 15-item self-reported questionnaire, the International Index of Erectile Function (IIEF).8 Sildenafil (Viagra; Pfizer, New York, NY, USA) was the first PDE5 inhibitor approved for treatment of ED in the US in 1998 and Taiwan in 1999. Tadalafil (Cialis; Lilly ICOS, Indiana, IN, USA) and vardenafil (Levitra; Bayer AG, Leverkusen, Germany) were approved in Taiwan in 2003. Pharmacotherapy with PDE5 inhibitors has the advantages of easy administration and good effectiveness with minimal side effects, which brought a revolutionary change in the treatment of ED.9 3. Safety and efficacy of PDE5 inhibitors PDE5 inhibitors are probably the best studied in well-designed clinical trials on the planet.10 Most currently available evidence
The success of the first generation of PDE5 inhibitors has stimulated the development and marketing of more new PDE5 inhibitors (Table 1) that provide greater flexibility for physicians and patients in clinical use. Udenafil16 (Zydena; Dong-A Pharmaceutical Co., Seoul, Korea) has a relatively rapid onset [time to maximum concentration (Tmax) ¼ 1e1.5 hours] and a long duration of action (T1/2 ¼ 11e13 hours; Table 2), and can be used on demand or once daily.17 To date, udenafil is approved only in Korea, Russia, and the Philippines. Avanafil (Stendra or Spedra; Vivus, Mountain View, CA, USA) has the advantage of rapid onset (Tmax 35 minutes) and a short half-life (< 1.5 hours)18 compared with other PDE5 inhibitors. Avanafil was approved by the United States Federal Drug Administration (FDA) in 2012 and by the European Medicines Agency in 2013. Mirodenafil (SK Chemicals Life Science, Seoul, South Korea) is characterized by its selectivity toward PDE5 being 10-fold higher than that of sildenafil, whereas its inhibitory effects on other PDEs were much lower than those of sildenafil in preclinical studies.19 Mirodenafil was approved in Korea in 2007.20 5. New formulation The oral route of administration is the most convenient and popular for most therapeutic agents. Conventional PDE5 inhibitors are produced as solid film-coated tablets and have to be swallowed with water. Oral dispersible tablets (ODTs) provide a novel and an attractive formulation, dissolving or disintegrating rapidly in the oral cavity. Compared to conventional film-coated tablets, ODT formulation has several advantages, including rapid onset, easier administration (without water), bypassing the gastrointestinal tract and hepatic portal systems, and better patient compliance.21 ODTs have a palatable flavor because of oral dissolving, avoiding a bitter taste and a connection with taking a pill for sex. Levitra ODT (10 mg) was the first PDE5 inhibitor introduced in ODT formulation with a minty taste in 2011. A pharmacokinetic study demonstrated that taking vardenafil ODT without water can
Please cite this article in press as: Jiann B-P, Evolution of phosphodiesterase type 5 inhibitors in treatment of erectile dysfunction in Taiwan, Urological Science (2016), http://dx.doi.org/10.1016/j.urols.2016.04.003
B.-P. Jiann / Urological Science xxx (2016) 1e5 Table 1 Advances in the phosphodiesterase type 5 inhibitors in clinical use. Variables
Remarks (Agents approved)
Agents
1st generation: sildenafil, tadalafil, & vardenafil 2nd generation: udenafil, avanafil, & mirodenafil Traditional: film-coated (all agents) New: orodispersible tablet (vardenafil, sildenafil, & mirodenafil) Traditional: on demand (all agents) New: daily dosing (tadalafil) 1. Erectile dysfunction (all the agents) 2. Pulmonary artery hypertension (sildenafil & tadalafil) 3. Lower urinary tract symptoms secondary to benign prostatic hyperplasia (tadalafil)
Formulation Dosing Indications
Table 2 Pharmacokinetics of the phosphodiesterase type 5 inhibitors. Agents
Cmax ng/mL
Tmax (h)
T1/2 (h)
Sildenafil 100 mg Tadalafil 20 mg Vardenafil 20 mg Udenafil 100 mg Avanafil 100 mg Mirodenafil 100 mg
450 378 20.9 416.2 871 373.4
0.8 2 0.7e0.8 1e1.5 0.5e1.5 1.25
3e5 17.5 4e5 11e13 <1.5 2.5
Cmax ¼ maximum plasma concentration; Tmax time to reach Cmax; T1/2 ¼ half-life.
increase bioavailability by 21e44% in the area under the plasma concentrationetime curve, compared with film-coated tablets in men with ED.22 Integrated analyses of two pivotal trials of Levitra ODT demonstrated its effectiveness and safety in men with ED and its time to onset of action was comparable to that of film-coated tablets.23,24 Sildenafil ODT (50 mg) with a lemon flavor was introduced in Taiwan in 2015. Pharmacokinetic studies showed no significant difference between sildenafil ODTs and film-coated tablets.25,26 The study also showed that a high-fat meal reduced absorption of ODT and therefore sildenafil ODT should be taken on an empty stomach.26 However, no study has been conducted to prove whether ODT formulation is preferred over conventional film-coated formulation in clinical practice. 6. Route of administration Sildenafil was the first drug designed for use only if necessary (on demand), although initially it was designed to be taken three times daily. ED patients have to take sildenafil or vardenafil 1 hour before and tadalafil 2 hours before sexual activity, considering the onset and Tmax (Table 2). The therapeutic window may last for 12 hours for 100 mg sildenafil,27 10 hours for 20 mg vardenafil,28 and 36 hours for 20 mg tadalafil,29 which is approximately two times their half-life (Table 2). Taking a pill before sexual activity does not necessarily represent successful sexual intercourse. Sexual activity may be influenced by the behavioral complexity of sexual intimacy, such as the communication and coordination around the frequency, timing and initiation of sexual activity.30,31 A large population survey in Eastern countries revealed that 50% of men did not want to plan their sexual activity.32
3
A longer duration of therapeutic window allows more spontaneity for sex and more time to look for the optimal moment for sex than a shorter therapeutic window. Tadalafil has the longest halflife (17.5 hours) among the PDE5 inhibitors. The first study of daily dosing of tadalafil 10 mg or 20 mg was conducted to salvage previously unresponsive to on-demand tadalafil and 60% of patients converted to responders.33 A pharmacokinetic study showed that at the simulated steady state, tadalafil 5 mg once daily provided plasma concentrations > 55 ng/mL, and ~90% enzyme inhibition in vitro,34 which is similar to those observed 24 hours after tadalafil 20 mg two or three times weekly.35 An integrated analysis of data from six randomized, placebo-control trials showed that improvement rate in mild, moderate, and severe ED after taking tadalafil 5 mg once daily was 74.8%, 63.1%, and 44.5%, respectively.36 The response rate in men with ED showed no significant difference between tadalafil on demand and once daily; however, a lower incidence of treatment-emergent adverse events ( 4%) was reported for tadalafil once daily because of a lower peak plasma concentration than on demand.37,38 The differences in clinical effect of PDE5 inhibitors administered on demand or daily for the treatment of ED are compared in Table 3.
7. New clinical indications According to the classification of the World Health Organization, pulmonary hypertension has five classes: idiopathic pulmonary arterial hypertension (PAH) and the remaining four groups with different etiologies. Patients with PAH have two important features in the pulmonary vasculature: increased expression of the vasoconstrictor PDE5 and decreased production of the vasodilator NO.39 An illustrative trial (SUPER-1 trial)40 and an open-label 3-year extension trial (SUPER-2 trial)41 established the efficacy of sildenafil in the treatment of PAH. Compared with placebo, sildenafil improved 6-minute walking distance, mean pulmonary artery pressure, and functional class in a dose-dependent fashion. The FDArecommended dose for sildenafil for treatment of PAH is 20 mg three times daily. Tadalafil also demonstrated its clinical improvement in PAH in the PHIRST-142 and -243 trials. The FDA-recommended dose for treatment of PAH is tadalafil 40 mg daily. Vardenafil is not approved by the FDA for the treatment of PAH, although clinical improvement was also demonstrated in the trial.44 Altitude sickness consists of three syndromes: acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema (HAPE). HAPE usually occurs at altitudes > 3000 m in rapidly ascending nonacclimatized individuals within the first 2e5 days after arrival.45 The prevalence of HAPE depends on the degree of susceptibility, rate of ascent, and final altitude. Rapid ascent is the most important and modifiable risk factor. HAPE is the leading cause of death from altitude sickness, but can be prevented by careful ascent and reversed with early recognition and treatment. Placebo-controlled trials confirmed that taking sildenafil or tadalafil can significantly reduce the incidence of HAPE.46,47 PDE5 inhibitors (sildenafil and tadalafil) have been shown to be effective and safe in the treatment and prevention of HAPE.48
Table 3 Differences in clinical effect of phosphodiesterase type 5 inhibitors administered on demand or daily for treatment of erectile dysfunction. Variables
On-demand administration
Once daily administration
Time frame for sex Sexual frequency Incidence of treatment-emergent adverse effects Peak plasma concentration of agent Treatment expenditure Beneficial effects on lower urinary tract symptoms
Yes For all sexual frequencies Higher Adequate Relatively lower Intermittent
Spontaneity, no time frame Appropriate for men with high sexual frequency Lower May not be enough for men who are considered difficult to treat Higher Constant
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ED and lower urinary tract symptoms (LUTSs) secondary to benign prostatic hyperplasia (BPH) are common medical diseases in men older than 50 years. Epidemiological studies suggest there is a strong correlation between both of them.49 mRNA expression for PDE5 has been demonstrated in rat lower urinary tract tissue.50 Sildenafil, tadalafil, and vardenafil dose-dependently reduced contraction of isolated bladder and urethral and prostate strips in animal studies,50 and clinical studies showed improvement in LUTSs.51 Nevertheless, only tadalafil 5 mg once daily is approved for the treatment of LUTSs secondary to BPH with or without ED. An integrated analysis of pooled data from four randomized, placebocontrolled tadalafil clinical studies demonstrated that significant improvement in ED (assessed by the IIEF) and LUTSs [assessed by the International Prostate Symptom Score (IPSS)] were confirmed regardless of baseline severity and improvements in the total IPSS and the IIEF-Erectile Function domain score were weakly correlated.52 Combined use of PDE5 inhibitor and a-blockers provided additive favorable effects in symptomatic relief compared with PDE5 inhibitor monotherapy.53 Long-term results for combination of tadalafil with a-blockers for the treatment of ED and BPH in men is still lacking. Prescribing daily PDE5 inhibitors for the treatment of LUTSs secondary to BPH faces a major challenge of costeffectiveness compared with a-blockers in clinical practice. 8. Conclusions PDE5 inhibitor is the most popular form for treatment of ED. More new PDE5 inhibitors, new preparation methods of agents and daily dosing provide more flexibility in clinical treatment for ED patients and physicians. Moreover, the clinical indications of PDE5 inhibitors have extended from ED to PAH and LUTSs secondary to BPH. Possible future indications for versatile PDE5 inhibitors are still developing that may provide new solutions for diseases in the future.
Conflict of interest Dr. Jiann gets grant and research support from Eli-Lilly and Pfizer Pharmaceuticals. Dr. Jiann is also an invited speaker for Pfizer, Eli-Lilly, Bayer, Menarini, and Orient Pharmaceuticals.
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Please cite this article in press as: Jiann B-P, Evolution of phosphodiesterase type 5 inhibitors in treatment of erectile dysfunction in Taiwan, Urological Science (2016), http://dx.doi.org/10.1016/j.urols.2016.04.003