Avanafil is a new FDE-5 inhibitor

The latest research shows that erectile dysfunction (ED) affects no less than 50% of men over 40 years old. ED significantly impacts a man's quality of life, self-esteem, psychosocial state, work performance, and also has negative effects on his sexual partner. The pathogenesis of ED is complex, involving many components, with the participation of central and peripheral nervous, endocrine, cardiovascular systems. Any dysfunction in these systems (due to medications, illness, etc.) can disrupt a man's ability to achieve or maintain penile erection, ejaculate, and experience orgasm.

The most common and important cause of ED is vascular damage. Many men with ED have identifiable risk factors for cardiovascular diseases (CVD) and various comorbidities: smoking, hipercholesterolemia, arterial hypertension, diabetes mellitus, ischemic heart disease. The consensus of the Princeton III experts recommends that men with ED should be screened for CVD risk factors, as ED can be an early sign of vascular atherosclerosis and vascular damage. The pathophysiology of ED is also related to genetic factors. Experimental animal model studies have shown that certain specific genes are activated at critical moments and begin to promote the production of certain proteins that influence erection. Genetic studies on human ED have not yet been conducted, but in the future, they may offer new effective methods and means of ED treatment. Currently, complete ED is defined as the total inability of a man to achieve and maintain penile erection during sexual stimulation and the absence of nocturnal erections. According to various studies, complete ED occurs in 10% of men, while varying degrees of ED affect 52% of men. Surveys show that 17% of men have mild ED, while 25% have moderate ED. 18-30 million American men have varying degrees of ED.

Possibilities of pharmacological treatment for erectile dysfunction

Currently, the primary drugs for treating ED are phosphodiesterase 5 (PDE-5) inhibitors. The first PDE5 inhibitor is sildenafil (approved in 1998), the newest one is avanafil (Spedra). The U.S. Food and Drug Administration (FDA) approved avanafil in April 2012. Avanafil (Spedra) stands out for its rapid onset of action, high efficacy, and particularly favorable safety profile. A study involving 360 men with diabetes and ED showed that avanafil (Spedra) begins to work (causing an erection) within 15 minutes and its effects last for at least 6 hours after ingestion. The latest guidelines from the American Urological Association (AUA) indicate that PDE-5 inhibitors are optional drugs for treating ED, except in cases where these drugs are contraindicated. If treatment with one PDE-5 inhibitor is not sufficiently effective, another PDE-5 inhibitor (such as avanafil (Spedra)) may be recommended to the patient, or prostaglandin E1 (alprostadil) injections into the penile corpora cavernosa or urethra can be administered together with a PDE-5 inhibitor. Other pharmacological class drugs used or recently introduced for the treatment of erectile dysfunction include: vascular endothelial growth factors, adrenergic receptor antagonists (phentolamine, delequamine, yohimbine), dopamine receptor antagonists (apomorphine, bromocriptine), serotonin receptor agonists (trazodone), xanthine derivatives (pentoxifylline), oxytocin receptor stimulants (oxytocin).

Avanafil

Avanafil (Spedra) is a highly active PDE-5 inhibitor characterized by rapid onset of action and exceptional safety. In case of mild or moderate hepatic or renal insufficiency, no dose adjustment of avanafil (Spedra) is needed. It can be taken regardless of meals. Avanafil (Spedra) inhibits cGMP degradation and enhances the effect of NO on the relaxation of penile corpus cavernosum smooth muscles. PDE-5 inhibitors are usually well-tolerated, but a significant number of patients still discontinue their use. Several factors contribute to this:

• whether the treatment meets the patient's expectations for the drug to act quickly and effectively;

• the severity of ED and the effectiveness of the treatment;

• safety, tolerability;

• adherence to the prescribed treatment regimen.

The more selective a PDE-5 inhibitor is for PDE-5 receptors, the safer it is. PDE receptors are found in various organs and tissues: PDE-1 – in the heart, brain, vascular smooth muscles, PDE-6 – in the retina of the eye, PDE-11 – in skeletal muscles, prostate, liver, kidneys, pituitary gland, testes. Avanafil (Spedra) exhibits the highest selectivity for PDE-5 receptors. Avanafil blocks vascular PDE-1 receptors 10 times more selectively than tadalafil or vardenafil, and even 30 times more selectively than sildenafil. Avanafil is 10 times more selective for retinal PDE-6 receptors than vardenafil, and 4–5 times more selective for skeletal muscle PDE-11 receptors than vardenafil or sildenafil.

According to safety data from Mulhall et al. (2013), avanafil (Spedra) was safe and well-tolerated for individuals with severe comorbidities (post-radical prostatectomy). No cases of priapism or major cardiovascular complications were reported in any patient using avanafil (Spedra), and syncope occurred in < 2% of patients. Adverse effects such as headache, flushing, or nasopharyngitis were more frequently reported in patients taking 200 mg of avanafil (Spedra) compared to those taking 100 mg. Even when taken twice daily, no accumulation of the drug in plasma or signs of overdose were detected with avanafil (Spedra). Individuals with mild or moderate renal or hepatic impairment do not need to reduce avanafil (Spedra) doses, as the metabolism and pharmacokinetics of this drug are largely independent of the function of these organs. Food has no significant influence on the pharmacokinetics of avanafil (Spedra), so this drug can be taken regardless of meals, i.e., there is no need to adjust it according to a meal schedule or food products.

"Just in time" – at the right time

The sexual activity cycle consists of several stages:

• establishing contact with a partner (about 15 min.);

• preparation (about 30 min.);

• sexual stimulation (about 15 min.);

• sexual intercourse (typically 1 hour after contact; duration varies).

The need for penile hardening (erection) arises during the preparatory phase, especially during the period of sexual stimulation, i.e., 30-45 minutes after the start of contact. Avanafil (Spedra) begins to work after just 15 minutes, ensuring the satisfaction of erection needs during intimate communication between partners. Avanafil (Spedra) has a unique galenic and molecular structure, which ensures rapid absorption of the active substance and high selectivity for FDE-5 receptors. Avanafil (Spedra) has the shortest time to reach maximum plasma concentration of all FDE-5 inhibitors (0.5-0.75 hours). When taken orally, it starts to work on average after 30 minutes, but the effect on erectile function is already noticeable after 15 minutes. For comparison: sildenafil starts working after 60 minutes, tadalafil – no less than 30 minutes, vardenafil ODT (orally disintegrating tablets) – after 25-60 minutes, udenafil – after 60 minutes. The clinical study REVIVE/TA-301 showed that all doses of avanafil (Spedra 50, 100, and 200 mg) ensure a frequency of 60-83% successful sexual attempts within 15 minutes to 6 hours after the dose, with the 100-200 mg doses of avanafil (Spedra) significantly more effective than 50 mg. According to this study, any dose of avanafil was significantly more effective than placebo. Avanafil (Spedra) effectively improved erection even in individuals with diabetes. According to data from the REVIVE-Diabetes/TA-302 study, doses of 100-200 mg of avanafil (Spedra) ensured a frequency of 40-70% successful sexual attempts within 15 minutes to 6 hours after the dose. In patients after radical prostatectomy, avanafil (Spedra) ensured a successful sexual act in 36.4% of cases within 15 minutes of the dose, while placebo did so in 4.5% of cases.

**Conclusions**

- The safety of FDE-5 inhibitors directly depends on the selectivity of FDE-5 enzyme inhibition.
- Studies show that avanafil (Spedra) does not exhibit clinically significant adverse effects typical of other FDE-5 inhibitors, for example, it practically does not cause dyspepsia.
- Avanafil (Spedra) significantly improves erectile function in all severity levels of erectile dysfunction (mild, moderate, or severe), including patients with difficult-to-treat erectile dysfunction (diabetic or post-prostatectomy patients). All available doses of avanafil on the market (Spedra 50, 100, or 200 mg) are significantly more effective than placebo.
- Avanafil (Spedra) begins to work after 15 minutes and lasts for at least 6 hours after the dose.
- The pharmacokinetic and pharmacodynamic properties of avanafil (Spedra) ensure the safety of this drug and greatly reduce the likelihood of potential misuse.
- In cases of impaired kidney or liver function, the effectiveness and safety of avanafil (Spedra) do not change. Dose adjustment of avanafil (Spedra) is not necessary in cases of kidney or liver insufficiency.
- There is evidence that avanafil (Spedra) may even improve the function of the liver or kidneys in case of dysfunction of these organs.

Based on the lecture "Avanafil a new FDE-5 inhibitor" presented by Dr. J. Kastys at the European Association of Urology Congress of the Baltic Countries in Vilnius on May 23-25, 2014, prepared by B. Djavan.