Avanafil

Avanafil is a potent and selective inhibitor of phosphodiesterase type 5 (PDE5) with IC50 value of 5.2nM [1].

PDE5 is abundantly expressed in penile corpus cavernosum and regulates penile blood flow by regulating the cGMP concentration. PDE5 inhibitors are similar in structure to cGMP and competitively bind to PDE5, resulting in the inhibition of cGMP hydrolysis. Avanafil is a high selective inhibitor of PDE5 with Ki value of 4.3nM and is developed for the treatment of erectile dysfunction. It shows high selectivity against other PDE enzymes of the PDE family. In the intravenous study, the administration of avanafil at 300μg/kg can potentiate penile tumescence. The calculated ED200% of avanafil on tumescence is 37.5μg/kg and the plasma concentration is 59.6ng/ml. Additionally, avanafil potentiates penile tumescence at a dose range of 100 to 1,000μg/kg intraduodenally. And the ED200% is 151.7μg/kg [1, 2].

References:
[1] Kotera J, Mochida H, Inoue H, Noto T, Fujishige K, Sasaki T, Kobayashi T, Kojima K, Yee S, Yamada Y, Kikkawa K, Omori K. Avanafil, a potent and highly selective phosphodiesterase-5 inhibitor for erectile dysfunction. J Urol. 2012 Aug;188(2):668-74.
[2] Cui YS, Li N, Zong HT, Yan HL, Zhang Y. Avanafil for male erectile dysfunction: a systematic review and meta-analysis. Asian J Androl. 2014 May-Jun;16(3):472-7.

Avanafil for the treatment of erectile dysfunction.[Pubmed:27416913]

Expert Rev Clin Pharmacol. 2016 Sep;9(9):1163-70.

INTRODUCTION: Erectile dysfunction (ED) affects millions of men worldwide, and the incidence of ED will continue to increase as the aging population grows. The first generation of phosphodiesterase-5 (PDE5) inhibitors, the mainstay of oral ED therapy, has revolutionized the treatment of this condition, but not without some drawbacks. Avanafil, the only United States and European Union-approved second-generation PDE5 inhibitor, is a safe and efficacious alternative to its predecessors. AREAS COVERED: We reviewed the current and most up-to-date literature regarding Avanafil, as well as the pivotal trials that measured efficacy and tolerability. As Avanafil is still a relatively new drug, there is still a relative paucity of literature which inherently limited the search parameters. We searched the PUBMED database for articles detailing the clinical trials, chemistry, pharmacokinetics and dynamics, safety, and efficacy of the drug. Expert commentary: Avanafil's unique pharmacologic profile both narrows and minimizes side effects while reducing the time of onset of action to half of its closest competitor, providing men who suffer with ED a return to a more spontaneous sex life.

Effects of different combinations of nanocrystallization technologies on avanafil nanoparticles: in vitro, in vivo and stability evaluation.[Pubmed:27939570]

Int J Pharm. 2017 Jan 30;517(1-2):148-156.

The study investigated the effects of different combined top-down and bottom-up nanocrystallization technologies on particle size and solid state of Avanafil nanoparticles. Combined antisolvent precipitation-ultrasonication (sonoprecipitation) technique was adopted to prepare 18 formulas according to 3(2).2(1) factorial design using 3 stabilizers; Tween 80, polyvinyl alcohol (PVA) and Pluronic F68 at different concentrations with different cryoprotectants. Particle size analysis of the lyophilized formulas showed that Tween 80 was an effective nanoparticles stabilizer in contrast to Pluronic F68 and PVA which failed to prevent nanoparticles flocculation when they were used at high concentration. The combined effects of nanonization and amorphism contributed to the improvement in solubility. Further processing of the sonoprecipitated formulas by high pressure homogenization (HPH) (modified NANOEDGE technology) resulted in further size reduction of PVA-stabilized particles, while it stimulated flocculation of Tween-stabilized nanoparticles. Nevertheless, all of the homogenized formulas partially retrieved their crystallinity which reduced their solubility. Non-homogenized formula 2E composed of 1:2 (Avanafil: Tween) with glucose as cryoprotectant, exhibited 13.68- and 2.59-fold improvement in solubility and in vitro dissolution, respectively. This formula had oral bioavailability of 137.02% relative to Spedra((R)) tablets and it maintained its nanosize, amorphism and dissolution behavior over 6 months of storage under stress conditions.

Formulation of avanafil in a solid self-nanoemulsifying drug delivery system for enhanced oral delivery.[Pubmed:27590128]

Eur J Pharm Sci. 2016 Oct 10;93:447-55.

Avanafil was incorporated into solid self-nanoemulsifying systems with the aim of improving its oral bioavailability. Labrafil, Labrafac, and Miglyol 812 N were investigated as oils, Tween 80 and Cremophor EL as surfactants, and Transcutol HP as a co-surfactant. Nine formulations produced clear solutions of 13.89-38.09nm globules after aqueous dilution. Adsorption of preconcentrate onto Aeroperl 300 Pharma at a 2:1 ratio had no effect on nanoemulsion particle size. Differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy indicated that Avanafil was molecularly dispersed within the solid nanosystems. A formulation containing 10% Labrafil, 60% Tween 80, and 30% Transcutol HP had the highest drug loading (44.48mg/g) and an acceptable in vitro dissolution profile (96.42% within 30min). This formulation was chemically and physically stable for 6months under accelerated storage conditions and it produced a 3.2-fold increase in bioavailability in rabbits, as compared to conventional commercially available Avanafil tablets (Spedra((R))).

Effect of different polymers on avanafil-beta-cyclodextrin inclusion complex: in vitro and in vivo evaluation.[Pubmed:27576665]

Int J Pharm. 2016 Oct 15;512(1):168-177.

In this study, we examined the effect of different polymers on the chemical, physical and pharmacokinetic properties of Avanafil-beta-cyclodextrin (beta-CD) inclusion complex. Equimolar mixtures of drug and beta-CD were used to prepare 25 ternary drug-beta-CD-polymer inclusion complexes using five different polymers, polyethylene glycol (PEG 4000), polyvinyl pyrrolidone (PVP K-30), chitosan, hydroxypropylmethyl cellulose, and hydroxyethyl cellulose, each in five different concentrations, 1, 3, 5, 7, and 10% (w/w). The addition of 10% (w/w) PEG 4000 resulted in a significant decrease of drug solubility, where the infrared spectra and differential scanning thermograms revealed an interaction between PEG 4000 and Avanafil which hindered drug inclusion. In contrast, addition of 7% (w/w) PVP K-30 facilitated drug inclusion as concluded from differential scanning thermograms, X-ray diffraction patterns and scanning electron micrographs. This resulted in a subsequent improvement in drug solubility and in vitro dissolution. This formula was chemically and physically stable for 6 months under accelerated storage conditions. The formula had a relative bioavailability of 125.56% in rabbits as compared to conventional commercially available Avanafil tablets (Spedra((R))).

Avanafil(TA-1790) is a potent and highly selective phosphodiesterase-5(PDE-5) inhibitor(IC50=5.2 nM) for erectile dysfunction; lower selectivity against PDE1, PDE6, and PDE11.

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