The first-generation phosphodiesterase 5 inhibitors and their pharmacokinetic issue

Andrology. 2019 Nov;7(6):804-817. doi: 10.1111/andr.12683. Epub 2019 Jul 26.


Background: Erectile dysfunction (ED) is a relatively frequent disease that negatively impacts the overall quality of life, well-being, and relationships. Although the use of phosphodiesterase 5 inhibitors (PDE5is) has revolutionized the treatment of ED, a high percentage of ED patients discontinue PDE5i treatment.

Objectives: (i) To analyze the reasons for patient dissatisfaction leading to PDE5i discontinuation; (ii) analyze the pharmacokinetics of new formulations focusing on the time needed to reach an effective plasma concentration of PDE5is (Tonset ) following drug intake; and (iii) summarize the physicochemical properties of sildenafil to understand which excipients may increase the absorption rate.

Material and methods: An online PubMed literature search was conducted to identify English language publications from inception to January 2019.

Results: The main reasons for patient dissatisfaction when using PDE5is on demand are the relatively long Tonset after taking vardenafil and sildenafil, including formulations such as film-coated tablets, fine granules, orally disintegrating tablets (ODTs), and oral thin films (ODFs). The relatively long Tonset , further worsened when accompanied by eating, highlights the following: (i) the need for planning intercourse, determining partner-related issues; (ii) issues when having sex before the maximum effect of the drug; and (iii) lower drug-related placebo effects. Some data suggest that sildenafil is a 'difficult' molecule, but Tonset can be improved following absorption by buccal mucosa using appropriate excipients.

Conclusions: We conclude that several ODT and ODF formulations can improve the 'discretion' issue because they are taken without water, but they have similar pharmacokinetics to corresponding film-coated tablet formulations. One ODF formulation of sildenafil was characterized by a shorter Tonset and could potentially increase patient satisfaction following treatment. However, more clinical studies are needed to confirm the findings. Surfactants and ascorbic acid appear to be crucial excipients for achieving a high absorption rate, but more studies are needed.

Keywords: ODF formulation; OTF formulation; PDE5 inhibitors; erectile dysfunction; excipients; pharmacokinetic.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Administration, Mucosal
  • Adult
  • Aged
  • Aged, 80 and over
  • Erectile Dysfunction / drug therapy*
  • Erectile Dysfunction / epidemiology
  • Humans
  • Male
  • Middle Aged
  • Mouth Mucosa / physiology
  • Patient Compliance / psychology*
  • Patient Satisfaction
  • Phosphodiesterase 5 Inhibitors / pharmacokinetics*
  • Phosphodiesterase 5 Inhibitors / therapeutic use
  • Quality of Life
  • Sexual Behavior / drug effects
  • Sildenafil Citrate / pharmacokinetics*
  • Sildenafil Citrate / therapeutic use
  • Tadalafil / pharmacokinetics*
  • Tadalafil / therapeutic use
  • Vardenafil Dihydrochloride / pharmacokinetics*
  • Vardenafil Dihydrochloride / therapeutic use


  • Phosphodiesterase 5 Inhibitors
  • Vardenafil Dihydrochloride
  • Tadalafil
  • Sildenafil Citrate