The first‐generation phosphodiesterase 5 inhibitors and their pharmacokinetic issue

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 (T(onset)) 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 T(onset) 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 T(onset), 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 T(onset) 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 T(onset) 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.