Avanafil

Absorption

Avanafil is rapidly absorbed following oral administration (Tmax of 30-45 minutes) and appears to have low to moderate oral bioavailability, though formal studies have not been conducted. Administration with a meal results in a mean delay in Tmax of 1.12 to 1.25 hours, a 39% mean reduction in Cmax, and a negligible effect on AUC.

Toxicity

Experience with avanafil overdose is limited. Single doses of up to 800mg and repeat doses of up to 300mg have been administered - these patients experienced adverse effects similar to those seen at therapeutic doses but with increased incidence and severity. Patients experiencing an overdosage of avanafil should be treated with standard symptomatic and supportive measures. Dialysis is unlikely to be of benefit in cases of overdose as avanafil is highly protein-bound in plasma.

Description

Avanafil (Zepeed) was approved by the Korean Health Ministry for the treatment of erectile dysfunction (ED) in August 2011. Avanafil is a highly selective type 5 phosphodiesterase (PDE5) inhibitor. Avanafil is reported to be the most selective PDE5 inhibitor on the market. The onset of Tmax and half-life also varies among the marketed PDE5 inhibitors. Sildenafil has a T_max at 1 h and a half-life of 3–5 h. Vardenafil is somewhat similar with a T_max of 0.6 h and a half-life of 4–6 h. Tadalafil has the longest half-life among the marketed drugs with a half-life of 17 h. Avanafil has a fast onset of action reaching T_max in 0.6 h with a half-life of 1.2 h. A synthesis of avanafil (TA-1790) is described in the patent literature. The main elimination route of avanafil is through the bile and feces. Avanafil was also found to be reabsorbed through enterohepatic recirculation.

The Uses of Avanafil

Avanafil is a highly selective PDE5 inhibitor with IC50 of 1 nM.

Indications

Avanafil is indicated for the treatment of erectile dysfunction.

What are the applications of Application

Avanafil is a derivative of pyrimidine that acts as PDE5 (phosphodiesterase-5) inhibitor

Background

Avanafil is a phosphodiesterase-5 (PDE5) inhibitor used in the treatment of erectile dysfunction. In comparison with other drugs of the same class, it shows greater selectivity for PDE5 over PDE6 than both sildenafil and vardenafil but less selectivity than tadalafil, suggesting a relatively lower risk of visual disturbances associated with off-target PDE6 inhibition.
It first received FDA approval on April 27, 2012, with subsequent EMA approval in June 2013.

Pharmacokinetics

Avanafil is a strong competitive inhibitor of phosphodiesterase 5 (PDE5) with a demonstrated in vitro IC50 of 5.2 nM. Its inhibitory effects on PDE5 are 100-fold more potent than on PDE6 and >1000-fold more potent than on other PDE enzymes, meaning it is less likely to cause visual disturbances and cardiovascular adverse effects when compared with less selective PDE5 inhibitors such as sildenafil and vardenafil. It has a relatively quick onset of action allowing for administration as early as 15 minutes prior to sexual activity.
PDE5 inhibitors like avanafil can cause significant drug interactions when administered alongside certain antihypertensive agents (e.g. alpha blockers, substantial amounts of alcohol). PDE5 inhibitors have also been associated with the development of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition that typically presents as sudden loss of vision in one or both eyes and appears to be more common in patients with a "crowded" optic disc. Patients presenting with any degree of vision loss should immediately discontinue use of all PDE5 inhibitors and seek medical attention. In some jurisdictions, a history of NAION or other degenerative retinal disorders is considered a contraindication to avanafil therapy.

Metabolism

Avanafil is extensively metabolized, primarily by CYP3A4 and to a lesser extent by CYP2C9. There are two major metabolites formed, M4 and M16, which exist in the plasma at concentrations 23% and 29% that of the parent compound, respectively. The M16 metabolite lacks pharmacologic effect, but the M4 metabolite has an inhibitory potency for PDE5 18% that of avanafil and accounts for approximately 4% of the observed pharmacologic activity of avanafil.